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Louisiana State University
1.
Theivanthiran, Balamayooran.
Role of NOD2/RIP2 signaling in acute bacterial pneumonia and sepsis.
Degree: PhD, Veterinary Pathology and Pathobiology, 2013, Louisiana State University
URL: etd-04102013-190507
;
https://digitalcommons.lsu.edu/gradschool_dissertations/638 
► Bacterial pneumonia and sepsis are two important causes of mortality in the world. Emergence of multidrug resistant bacteria has necessitated the development of new treatment…
(more)
▼ Bacterial pneumonia and sepsis are two important causes of mortality in the world. Emergence of multidrug resistant bacteria has necessitated the development of new treatment and/or prevention strategies to augment host immune defense. In this context, the innate host defense is critical in clearing pathogenic bacteria from the host. Early neutrophil recruitment is a critical step in a multistep requence leading to bacterial clearance. Pattern recognition receptors (PRRs) play a critical role in the innate immune system. Receptor interacting protein 2 (RIP-2) is an adaptor for the nod-like receptors (NLR) NOD1 and NOD2. Nucleotide oligomerisation domain 2 (NOD2) is an intracellular PRR that is shown to be important for host defense against intracellular bacterial pathogens. However, the role of NOD2 and RIP-2 during Gram-negative bacterial pneumonia and polymicrobial sepsis has not been explored. Thus, we hypothesize that the NOD2/RIP-2 axis is critical for host defense during bacterial pneumonia and sepsis/septic peritonitis. To test this hypothesis, we infected NOD2(NOD2-/-), RIP-2(RIP-2-/-) deficient mice intratracheally (i.t) with E. coli (106 CFUs/mouse) and Klebsiella pneumoniae (103 CFUs/mouse). We observed that NOD2/RIP2 signaling is critical for the host defense during gram-negative pneumonia and poly microbial sepsis. The NOD2/RIP2 axis regulates neutrophil recruitment via IL-17A production. We also found that NOD2/RIP-2 signaling is essential for the production of IL-6 and activation of STAT3. We demonstrated that RIP-2 regulates inflammasome activity that is independent of NOD2 signaling. Taken together, these data demonstrate that the NOD2/RIP-2 axis plays a critical role in neutrophil-mediated host defense through IL-17A production and by inflammasome activation. In cecal ligation puncture (CLP) induced sepsis, RIP2-/- mice show increased mortality with higher bacterial burden in the peritoneum and systemic organs compared to WT controls. We found reduced neutrophil influx IL-17A and IL-1beta levels in the peritoneum of RIP2-/- mice after CLP. Furthermore, we also observed increased systemic inflammation accompanied by vital organ damage in the knockout mice. As a whole our data suggest a critical role of RIP2 in neutrophil recruitment, along with IL-17A and IL-1beta during sepsis.
Subjects/Keywords: sepsis; bacteria; RIP2; NOD2; Pneumonia
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APA (6th Edition):
Theivanthiran, B. (2013). Role of NOD2/RIP2 signaling in acute bacterial pneumonia and sepsis. (Doctoral Dissertation). Louisiana State University. Retrieved from etd-04102013-190507 ; https://digitalcommons.lsu.edu/gradschool_dissertations/638
Chicago Manual of Style (16th Edition):
Theivanthiran, Balamayooran. “Role of NOD2/RIP2 signaling in acute bacterial pneumonia and sepsis.” 2013. Doctoral Dissertation, Louisiana State University. Accessed March 09, 2021.
etd-04102013-190507 ; https://digitalcommons.lsu.edu/gradschool_dissertations/638.
MLA Handbook (7th Edition):
Theivanthiran, Balamayooran. “Role of NOD2/RIP2 signaling in acute bacterial pneumonia and sepsis.” 2013. Web. 09 Mar 2021.
Vancouver:
Theivanthiran B. Role of NOD2/RIP2 signaling in acute bacterial pneumonia and sepsis. [Internet] [Doctoral dissertation]. Louisiana State University; 2013. [cited 2021 Mar 09].
Available from: etd-04102013-190507 ; https://digitalcommons.lsu.edu/gradschool_dissertations/638.
Council of Science Editors:
Theivanthiran B. Role of NOD2/RIP2 signaling in acute bacterial pneumonia and sepsis. [Doctoral Dissertation]. Louisiana State University; 2013. Available from: etd-04102013-190507 ; https://digitalcommons.lsu.edu/gradschool_dissertations/638
University of Toronto
2.
Sorbara, Matthew Thomas.
Novel Functions of ATG16L1 in the Innate Response to Invasive Bacterial Pathogens.
Degree: PhD, 2016, University of Toronto
URL: http://hdl.handle.net/1807/89258
► Crohnâ s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract. Susceptibility to CD is determined by both environmental and genetic risk factors.…
(more)
▼ Crohnâ s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract. Susceptibility to CD is determined by both environmental and genetic risk factors. While the etiology of CD remains unclear, several pathways have been consistently implicated in susceptibility. Indeed, multiple genes involved in the innate immune response have been strongly linked to CD. Studies examining the function of these innate immune genes have indicated that an inability to properly handle bacteria that come into contact with the intestinal mucosa, as well as defects in the regulation of the inflammatory response triggered by innate recognition of these bacteria, are primary factors in increasing CD susceptibility. Autophagy, a degradation system for cytoplasmic cargo, has been implicated in both of these functions. ATG16L1 is a central component of the autophagy machinery and is a CD susceptibility locus. Here, two novel functions of ATG16L1 in the innate immune response are described. First, we uncovered a regulatory role for ATG16L1 in the inflammatory response driven by NOD1 and NOD2, which are intracellular sensors of bacterial invasion. Secondly, we identified an interaction between complement C3, the central component of the complement cascade, and ATG16L1. This interaction allows for efficient targeting of complement C3-coated invasive pathogens to the autophagy machinery. Both of these functions were impaired in cells expressing the CD-associated variant of ATG16L1. Overall, these findings indicate that dysfunction of ATG16L1 in both regulation of inflammation and defective handling of complement-coated intracellular bacteria might contribute to the generation of a harmful inflammatory state in the gastrointestinal tract.
2018-07-08 00:00:00
Advisors/Committee Members: Philpott, Dana J, Immunology.
Subjects/Keywords: ATG16L1; Autophagy; Infection; NOD1; NOD2; 0982
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APA (6th Edition):
Sorbara, M. T. (2016). Novel Functions of ATG16L1 in the Innate Response to Invasive Bacterial Pathogens. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/89258
Chicago Manual of Style (16th Edition):
Sorbara, Matthew Thomas. “Novel Functions of ATG16L1 in the Innate Response to Invasive Bacterial Pathogens.” 2016. Doctoral Dissertation, University of Toronto. Accessed March 09, 2021.
http://hdl.handle.net/1807/89258.
MLA Handbook (7th Edition):
Sorbara, Matthew Thomas. “Novel Functions of ATG16L1 in the Innate Response to Invasive Bacterial Pathogens.” 2016. Web. 09 Mar 2021.
Vancouver:
Sorbara MT. Novel Functions of ATG16L1 in the Innate Response to Invasive Bacterial Pathogens. [Internet] [Doctoral dissertation]. University of Toronto; 2016. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/1807/89258.
Council of Science Editors:
Sorbara MT. Novel Functions of ATG16L1 in the Innate Response to Invasive Bacterial Pathogens. [Doctoral Dissertation]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/89258
University of Iowa
3.
Ver Heul, Aaron Martin.
Molecular basis of Nod1 And Nod2 signaling.
Degree: PhD, Biochemistry, 2013, University of Iowa
URL: https://ir.uiowa.edu/etd/4784
► NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins 1 and 2) are related innate immune receptors responsible for initiating a response to bacterial infection. They…
(more)
▼ NOD1 and
NOD2 (nucleotide-binding oligomerization domain-containing proteins 1 and 2) are related innate immune receptors responsible for initiating a response to bacterial infection. They belong to a class of receptors known as Pattern Recognition Receptors (PRRs), which are germline encoded immune receptors that mediate various innate immune responses. These receptors recognize conserved microbial motifs known as Pathogen-Associated Molecular Patterns (PAMPs). The PRR-PAMP paradigm forms the bedrock of how innate immunity is understood today. As two of the first intracellular PRRs discovered, NOD1 and
NOD2 came to define an entire subclass of PRRs, the NOD-like receptors (NLRs). PRRs relay their signals through protein:protein interaction motifs that typically adopt a characteristic Death Domain (DD) fold. NOD1 and
NOD2 signal through their respective CAspase Recruitment Domains (CARDs), which are part of a DD subfamily. The CARDs of NOD1 and
NOD2 interact with multiple downstream effectors and are thus situated at a key point for regulation and coordination of NOD1 and
NOD2 signaling. To better understand this regulation, I structurally and functionally characterized interactions made by the CARDs of NOD1 and
NOD2. Receptor Interacting Protein kinase 2 (RIP2) is an effector of both NOD1 and
NOD2 that activates the NF-ΚB pathway to elicit an inflammatory response. I discovered a new binding interaction between the CARDs of NOD1 and
NOD2 and ubiquitin. Furthermore, I elucidated a role for this interaction by showing that ubiquitin binds NOD1 and
NOD2 CARDs competitively with the CARD of RIP2. Through biophysical and biochemical investigation, I identified mutants of NOD1 CARD that did not bind ubiquitin and were thus insensitive to its competitive effect on RIP2 binding. Utilizing this mutant in functional studies defined ubiquitin as a negative regulator of NOD1 signaling. Characterizing NOD1 allowed rational design of mutations that uncovered a similar role for ubiquitin in the
NOD2 pathway. This introduces the potential for broader application of these findings in other DD-mediated pathways. NOD1 and
NOD2 also bind the autophagy protein ATG16L. I investigated the molecular mechanisms of this interaction and found that NOD1 and
NOD2 bind ATG16L through their CARDs. I also found that the domain on ATG16L responsible for binding NOD1 and
NOD2 is the C-terminal WD40 Β-propeller. Furthermore, the CARD:Β-propeller interaction is sufficient to mediate interaction between NOD1 or
NOD2 and ATG16L. The finding that the ATG16L Β-propeller also binds ubiquitin leaves open the possibility that ubiquitin regulates pathway selection by NOD1 and
NOD2. Together, these studies advance our understanding of NOD1 and
NOD2 signaling and lay the groundwork for further mechanistic investigations into coordination of inflammatory and autophagic signaling pathways by the immune system in general.
Advisors/Committee Members: Piper, Robert C. (supervisor).
Subjects/Keywords: Autophagy; Inflammation; NOD1; NOD2; Ubiquitin; Biochemistry
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APA (6th Edition):
Ver Heul, A. M. (2013). Molecular basis of Nod1 And Nod2 signaling. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/4784
Chicago Manual of Style (16th Edition):
Ver Heul, Aaron Martin. “Molecular basis of Nod1 And Nod2 signaling.” 2013. Doctoral Dissertation, University of Iowa. Accessed March 09, 2021.
https://ir.uiowa.edu/etd/4784.
MLA Handbook (7th Edition):
Ver Heul, Aaron Martin. “Molecular basis of Nod1 And Nod2 signaling.” 2013. Web. 09 Mar 2021.
Vancouver:
Ver Heul AM. Molecular basis of Nod1 And Nod2 signaling. [Internet] [Doctoral dissertation]. University of Iowa; 2013. [cited 2021 Mar 09].
Available from: https://ir.uiowa.edu/etd/4784.
Council of Science Editors:
Ver Heul AM. Molecular basis of Nod1 And Nod2 signaling. [Doctoral Dissertation]. University of Iowa; 2013. Available from: https://ir.uiowa.edu/etd/4784
4.
Lehtimaki, Mari.
Staphylococcus aureus as a source of antigens stimulating bovine dendritic cells and lymphocytes in vitro.
Degree: PhD, Animal Sciences, Dairy, 2017, Virginia Tech
URL: http://hdl.handle.net/10919/75153
► Staphylococcus aureus (S. aureus) is a gram-positive bacterium that causes mastitis in bovines and leads to financial losses to the dairy industry. Although antibody response…
(more)
▼ Staphylococcus aureus (S. aureus) is a gram-positive bacterium that causes mastitis in bovines and leads to financial losses to the dairy industry. Although antibody response plays a role in immune defense against S. aureus, cellular responses are of interest for vaccine development. A vaccine that stimulates both antibody and cellular responses could promote memory cell formation and provide effective protection against S. aureus. The superantigens and virulence factors secreted by live S. aureus (LSA) can interfere with immune responses and memory cell formation. Because irradiation reduces the metabolic activity and secretion of proteins, including S. aureus superantigens and hemolysins, we hypothesized the irradiated S. aureus (ISA) could drive immune cell responses.
Dendritic cells (DC) were co-cultured with lymphocytes to study the cellular responses to ISA and LSA. Dendritic cells present antigens and polarize lymphocytes into different helper T (Th) cell types that drive cellular immune responses. The DC loaded with either ISA or LSA induced increased mRNA transcription of Th17-related cytokines and cytotoxic effector memory cell formation during antigen recall experiments. Lymphocytes co-cultured with LSA-loaded DC exhibited a higher fold-change in interferon (IFN) γ mRNA compared to ISA-loaded DC, suggesting the secreted antigens and the metabolic activity of S. aureus play a role in Th1 polarization.
Th1 polarization can drive excessive inflammation and suppress beneficial Th17 responses. Bovine DC were stimulated with a mutant α-toxin deletion S. aureus strain to evaluate if α-toxin-mediated
NOD2 receptor signaling activates Th1 polarization in response to S. aureus, which revealed that
NOD2 mRNA transcription in DC was independent of α-toxin and that the deletion of α-toxin had no effect on the transcription of the cytokine IL-12 or the production of IFNγ by lymphocytes, events that drive Th1 polarization, in co-cultures. The deletion of accessory gene regulator (agr), which controls α-toxin production, reduced IFNγ production in lymphocytes co-cultured with the S. aureus-loaded DC, indicating that agr controlled the ability of S. aureus antigens to drive the Th1 polarization of lymphocytes.
Overall, this thesis demonstrates that ISA is a promising source of antigens that stimulate memory cells formation and Th17 polarization in bovine immune cells. The reduced Th1 cytokine response to S. aureus was not dependent on α-toxin, but other virulence factors controlled by agr should be screened to determine the source of Th1 stimulation.
Advisors/Committee Members: Kanevsky, Isis (committeechair), Luo, Xin (committee member), Akers, Robert Michael (committee member), Cranford, Jamie L. (committee member).
Subjects/Keywords: Staphylococcus aureus; DC; T helper cells; NOD2
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APA (6th Edition):
Lehtimaki, M. (2017). Staphylococcus aureus as a source of antigens stimulating bovine dendritic cells and lymphocytes in vitro. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/75153
Chicago Manual of Style (16th Edition):
Lehtimaki, Mari. “Staphylococcus aureus as a source of antigens stimulating bovine dendritic cells and lymphocytes in vitro.” 2017. Doctoral Dissertation, Virginia Tech. Accessed March 09, 2021.
http://hdl.handle.net/10919/75153.
MLA Handbook (7th Edition):
Lehtimaki, Mari. “Staphylococcus aureus as a source of antigens stimulating bovine dendritic cells and lymphocytes in vitro.” 2017. Web. 09 Mar 2021.
Vancouver:
Lehtimaki M. Staphylococcus aureus as a source of antigens stimulating bovine dendritic cells and lymphocytes in vitro. [Internet] [Doctoral dissertation]. Virginia Tech; 2017. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/10919/75153.
Council of Science Editors:
Lehtimaki M. Staphylococcus aureus as a source of antigens stimulating bovine dendritic cells and lymphocytes in vitro. [Doctoral Dissertation]. Virginia Tech; 2017. Available from: http://hdl.handle.net/10919/75153
5.
Frade Proud'hon-Clerc, Sara.
Recherche de nouvelles mutations génétiques à effet majeur dans la maladie de Crohn : Research of new major genetic mutations in Crohn's disease.
Degree: Docteur es, Génétique, 2019, Université Lille II – Droit et Santé
URL: http://www.theses.fr/2019LIL2S016
► Le gène NOD2, impliqué dans les réponses immunitaires innées contre le peptidoglycane bactérien, est étroitement associé à la maladie de Crohn (MC) avec des Odd…
(more)
▼ Le gène NOD2, impliqué dans les réponses immunitaires innées contre le peptidoglycane bactérien, est étroitement associé à la maladie de Crohn (MC) avec des Odd Ratio(OR) allant de 3 à 36 selon le génotype et a été initialement identifié par des analyses de liaisons génétiques. Les données des familles multiplexes (familles définies par la présence de trois ou plus de trois apparentés au premier degré atteints de MC) issues du registre EPIMAD ont été analysées. Il a été précédemment rapporté que dans les 22 familles multiplexes EPIMAD génotypées pour les 3 mutations majeures du gène NOD2une fréquence élevée de ces mutations du gène NOD2 : R702W, G908R et L1007fs, pouvait expliquer la fréquence élevée de MC dans ces familles. Cependant, quelques familles multiplexes EPIMAD ne présentaient aucune de ces mutations R702W, G908R et L1007fs.Afin d’identifier de nouvelles variations génétiques ayant un effet majeur dans la MC, un protocole de Whole Exome Séquencing (WES) a été effectué sur l’une de ces familles multiplexes EPIMAD (F49M) présentant quatre sujets atteints de MC sur deux générations.Une variation rare du gène NOD2, N1010K, s’est avérée présente chez tous les patients atteints et absente chez tous les sujets contrôles intrafamiliaux . L’évaluation in silico et la modélisation 3D ont mis en évidence un effet délétère hautement probable de la mutation de N1010K suggérant donc fortement qu’elle pourrait être un nouveau facteur de risque majeur impliqué dans la susceptibilité génétique à la maladie de Crohn. Elle pourrait expliquer l’agrégation familiale de la MC dans la famille analysée. La présence d’une maladie plus sévère chez les patients hétérozygotes composites N1010K/L1007fs plaide en faveur de l’effet délétère de la mutation N1010K.En plus de la caractérisation d’une nouvelle mutation rare du gène NOD2, 2 autres variants potentiels ont été identifiés : les mutations D359H et G33V respectivement des gènes BPIFB2 et DEFB132. Les protéines codées par ces gènes sont impliquées dans les mêmes voies de signalisation : la voie de signalisation des défensines ainsi que dans celle du système immunitaire inné. L’évaluation in silico des effet de ces mutations a mis en évidence un effet délétère hautement probable pour D359H et G33V des gènes BPIFB2et DEFB132. Ainsi, on peut supposer que bien que les deux mutations D359H du gèneBPIFB2 et G33V du gène DEFB132, soient localisés sur deux gènes différents impliquées dans les mêmes voies de signalisation, elles pourraient agir ensemble et conduire à un effet dysfonctionnel cumulatif impliqué également dans l’agrégation familiale de la MC dans la famille F49M.Ainsi, Pour la famille F49M, l’agrégation familiale pourrait reposer sur l’accumulation de plusieurs mutations à effet délétère (N1010K, D359H et G33V).
The NOD2 gene, involved in innate immune responses, has been found to be highlyassociated with Crohn’s Disease (CD). EPIMAD multiplex families with three or more CDaffectedmembers were previously reported to be related to a high frequency of NOD2gene mutations :…
Advisors/Committee Members: Vasseur, Francis (thesis director).
Subjects/Keywords: Maladie de Crohn; Gène NOD2; WES; Mutation; Crohn’s disease; NOD2 gene; WES; Variation
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APA (6th Edition):
Frade Proud'hon-Clerc, S. (2019). Recherche de nouvelles mutations génétiques à effet majeur dans la maladie de Crohn : Research of new major genetic mutations in Crohn's disease. (Doctoral Dissertation). Université Lille II – Droit et Santé. Retrieved from http://www.theses.fr/2019LIL2S016
Chicago Manual of Style (16th Edition):
Frade Proud'hon-Clerc, Sara. “Recherche de nouvelles mutations génétiques à effet majeur dans la maladie de Crohn : Research of new major genetic mutations in Crohn's disease.” 2019. Doctoral Dissertation, Université Lille II – Droit et Santé. Accessed March 09, 2021.
http://www.theses.fr/2019LIL2S016.
MLA Handbook (7th Edition):
Frade Proud'hon-Clerc, Sara. “Recherche de nouvelles mutations génétiques à effet majeur dans la maladie de Crohn : Research of new major genetic mutations in Crohn's disease.” 2019. Web. 09 Mar 2021.
Vancouver:
Frade Proud'hon-Clerc S. Recherche de nouvelles mutations génétiques à effet majeur dans la maladie de Crohn : Research of new major genetic mutations in Crohn's disease. [Internet] [Doctoral dissertation]. Université Lille II – Droit et Santé 2019. [cited 2021 Mar 09].
Available from: http://www.theses.fr/2019LIL2S016.
Council of Science Editors:
Frade Proud'hon-Clerc S. Recherche de nouvelles mutations génétiques à effet majeur dans la maladie de Crohn : Research of new major genetic mutations in Crohn's disease. [Doctoral Dissertation]. Université Lille II – Droit et Santé 2019. Available from: http://www.theses.fr/2019LIL2S016
6.
Aguilar, Claire.
Caractérisation de la pathologie intestinale associée au déficit en XIAP (X-linked inhibitor of apoptosis protein) : Characterization of the intestinal disease associated with XIAP (X-linked inhibitor of apoptosis protein) deficiency.
Degree: Docteur es, Immunologie, 2014, Université Paris Descartes – Paris V
URL: http://www.theses.fr/2014PA05T072
► Les mutations du gène codant pour la protéine XIAP (X-Linked Inhibitor of Apoptosis Protein) sont à l’origine du syndrome lymphoprolifératif lié à l’X de type…
(more)
▼ Les mutations du gène codant pour la protéine XIAP (X-Linked Inhibitor of Apoptosis Protein) sont à l’origine du syndrome lymphoprolifératif lié à l’X de type 2 (XLP-2). Il s’agit d’un déficit immunitaire rare caractérisé par une susceptibilité anormale à l’infection par le virus d’Epstein Barr (EBV). De plus, certains patients déficients en XIAP peuvent souffrir d’une pathologie intestinale parfois sévère. XIAP est molécule anti-apoptique qui a aussi été impliquée dans la signalisation et les fonctions de récepteurs de l’immunité innée, les récepteurs NOD1 et NOD2. Mon travail de thèse a eu pour objectif de caractériser cette pathologie intestinale et ses mécanismes physiopathologiques. Pour cela, nous avons étudié une cohorte de patients déficients en XIAP présentant une pathologie inflammatoire intestinale. Nous avons également recherché des mutations de XIAP dans une cohorte d’enfants ayant présenté comme unique signe clinique une pathologie intestinale précoce. Sur 83 patients testés, 3 patients porteurs de mutations de XIAP ont été identifiés. Nous avons ensuite montré que cette pathologie intestinale est très proche sur les plans clinique et histologique de la maladie de Crohn, qui est une des principales affections inflammatoires de l’intestin chez l’adulte. La maladie de Crohn est associée à des facteurs environnementaux et une susceptibilité génétique, dont les polymorphismes dans le gène NOD2 qui représentent le facteur plus important identifié à ce jour. Nous avons ensuite montré que les monocytes des patients déficients en XIAP ont un défaut de production d’IL-8, de MCP-1 et d’IL-10 en réponse à la stimulation de la voie NOD2. Par contre, nous n’avons pas mis en évidence d’excès d’apoptose des cellules épithéliales digestives chez les patients. En revanche, ils présentaient un nombre diminué de leur lymphocytes T innés circulants, Enfin, au cours de cette étude, nous avons identifié pour la première fois des femmes vectrices d’une mutation de XIAP à l’état hétérozygote, ayant développé des manifestations inflammatoires intestinales. Chez ces patientes, l’inactivation du chromosome X, qui normalement est biaisée en faveur de l’allèle sain chez les vectrices asymptomatiques, est de façon inhabituelle biaisée vers l’allèle muté contribuant à une diminution de l’expression de XIAP dans les monocytes et une altération de la voie NOD2. Ce travail a permis de montrer que le déficit en XIAP est responsable d’une forme monogénique de la maladie de Crohn. Nos résultats suggèrent que le défaut d’activation des monocytes par NOD2 est un mécanisme important de la pathogénèse de la maladie. Sur le plan thérapeutique, la greffe de moelle osseuse semble indiquée dans les formes sévères, puisque le principal défaut identifié est une anomalie du compartiment hématopoïétique, et chez deux de nos patients, elle a permis en effet une amélioration franche de la pathologie digestive qui était très sévère.
Mutations in the gene encoding for XIAP (X-Linked Inhibitor of Apoptosis Protein) are causing the X-linked…
Advisors/Committee Members: Latour, Sylvain (thesis director).
Subjects/Keywords: XIAP; Maladie de Crohn; NOD2; Apoptose; Allogreffe de cellules souches hématopoïétiques; XIAP; Crohn’s disease; NOD2; Apoptosis; Hematopoietic stem cell transplant; 617.554
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APA (6th Edition):
Aguilar, C. (2014). Caractérisation de la pathologie intestinale associée au déficit en XIAP (X-linked inhibitor of apoptosis protein) : Characterization of the intestinal disease associated with XIAP (X-linked inhibitor of apoptosis protein) deficiency. (Doctoral Dissertation). Université Paris Descartes – Paris V. Retrieved from http://www.theses.fr/2014PA05T072
Chicago Manual of Style (16th Edition):
Aguilar, Claire. “Caractérisation de la pathologie intestinale associée au déficit en XIAP (X-linked inhibitor of apoptosis protein) : Characterization of the intestinal disease associated with XIAP (X-linked inhibitor of apoptosis protein) deficiency.” 2014. Doctoral Dissertation, Université Paris Descartes – Paris V. Accessed March 09, 2021.
http://www.theses.fr/2014PA05T072.
MLA Handbook (7th Edition):
Aguilar, Claire. “Caractérisation de la pathologie intestinale associée au déficit en XIAP (X-linked inhibitor of apoptosis protein) : Characterization of the intestinal disease associated with XIAP (X-linked inhibitor of apoptosis protein) deficiency.” 2014. Web. 09 Mar 2021.
Vancouver:
Aguilar C. Caractérisation de la pathologie intestinale associée au déficit en XIAP (X-linked inhibitor of apoptosis protein) : Characterization of the intestinal disease associated with XIAP (X-linked inhibitor of apoptosis protein) deficiency. [Internet] [Doctoral dissertation]. Université Paris Descartes – Paris V; 2014. [cited 2021 Mar 09].
Available from: http://www.theses.fr/2014PA05T072.
Council of Science Editors:
Aguilar C. Caractérisation de la pathologie intestinale associée au déficit en XIAP (X-linked inhibitor of apoptosis protein) : Characterization of the intestinal disease associated with XIAP (X-linked inhibitor of apoptosis protein) deficiency. [Doctoral Dissertation]. Université Paris Descartes – Paris V; 2014. Available from: http://www.theses.fr/2014PA05T072
University of Delaware
7.
Lauro, Mackenzie L.
Molecular recognition of muramyl dipeptide by Nod2 and its implications in Crohn's disease and innate immunity.
Degree: PhD, University of Delaware, Department of Chemistry and Biochemistry, 2017, University of Delaware
URL: http://udspace.udel.edu/handle/19716/22637
► The human body hosts a fluctuating population of trillions of microorganisms. In order to provide a delicate balance with this enormous bacterial presence, the innate…
(more)
▼ The human body hosts a fluctuating population of trillions of microorganisms. In order to provide a delicate balance with this enormous bacterial presence, the innate immune system is charged with the recognition of immune triggering components. The innate immune system is comprised of a large number of receptors that work together to constantly survey the landscape of the cell for the presence of bacterial fragments. The synergy of this system is viewed as the first line of defense against invading pathogens. When there are disruptions to this intricate balance, disease susceptibility increases. One such disease that is proposed to arise from an atypical response to bacteria is Crohn’s disease (CD). CD is a debilitating, inflammatory bowel disorder for which there is no cure. CD patients suffer from a complex host of dysregulated interactions between their innate immune system and microbiome leading to bacterial dysbiosis and uncontrolled inflammation. ☐ The most predominant genetic link to the onset of CD is a mutation in the innate immune receptor nucleotide-binding oligomerization domain-containing 2 (
Nod2).
Nod2 responds to the presence of bacteria and stimulates the immune response. Mutations to
Nod2 promote low diversity and dysbiosis in the microbiome, leading to impaired mucosal barrier function. Current treatments suppress the immune response rather than enhancing the function of this critical protein. New progress toward stabilizing
Nod2 signaling through its interactions with small molecules holds potential in the development of novel CD therapeutics. ☐ There is limited biochemical and structural information about
Nod2 due to the complexities involved in isolating the recombinant protein.
Nod2 is a large, cysteine-rich protein that is membrane associated when activated. To overcome these challenges, a purification scheme utilizing a large solubility tag, glutathione-transferase, was employed. A well-folded, functional wild-type (WT)
Nod2 was produced from E. coli expression. WT
Nod2 demonstrated the ability to interact with Hsp70, a known binding partner. The human WT
Nod2 was suggested to co-purify with a natural ligand from the peptidoglycan of its expression host. ☐
Nod2 responds to the presence of bacteria, specifically a fragment of the bacterial cell wall, muramyl dipeptide (MDP). The proposed site of this interaction is the leucine-rich repeat (LRR) domain of
Nod2. Surface plasmon resonance (SPR) was used to investigate the interaction of the LRR domain with MDP. A functional and pure LRR domain was obtained from E. coli expression in high yield. The LRR domain binds to MDP with nM affinity. Fragment analysis of MDP revealed that both the peptide and carbohydrate portion contribute to the binding interaction with the LRR. Competition binding experiments confirmed that there is a specific binding interaction between the LRR and MDP. In addition, kinetic SPR experiments suggested that the fastest association to ligand requires the full MDP molecule. Slow dissociation times between
Nod2 and ligand…
Advisors/Committee Members: Bahnson, Brian J.Grimes, Catherine Leimkuhler.
Subjects/Keywords: Pure sciences; Crohn’s disease; Innate immunity; Molecular recognition; Muramyl dipeptide; Nod2
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APA (6th Edition):
Lauro, M. L. (2017). Molecular recognition of muramyl dipeptide by Nod2 and its implications in Crohn's disease and innate immunity. (Doctoral Dissertation). University of Delaware. Retrieved from http://udspace.udel.edu/handle/19716/22637
Chicago Manual of Style (16th Edition):
Lauro, Mackenzie L. “Molecular recognition of muramyl dipeptide by Nod2 and its implications in Crohn's disease and innate immunity.” 2017. Doctoral Dissertation, University of Delaware. Accessed March 09, 2021.
http://udspace.udel.edu/handle/19716/22637.
MLA Handbook (7th Edition):
Lauro, Mackenzie L. “Molecular recognition of muramyl dipeptide by Nod2 and its implications in Crohn's disease and innate immunity.” 2017. Web. 09 Mar 2021.
Vancouver:
Lauro ML. Molecular recognition of muramyl dipeptide by Nod2 and its implications in Crohn's disease and innate immunity. [Internet] [Doctoral dissertation]. University of Delaware; 2017. [cited 2021 Mar 09].
Available from: http://udspace.udel.edu/handle/19716/22637.
Council of Science Editors:
Lauro ML. Molecular recognition of muramyl dipeptide by Nod2 and its implications in Crohn's disease and innate immunity. [Doctoral Dissertation]. University of Delaware; 2017. Available from: http://udspace.udel.edu/handle/19716/22637
Freie Universität Berlin
8.
Xia, Yu.
Einfluss der nucleotide-binding Oligomerisation domain-containing protein 2
(Nod 2) auf die virale Myokarditis durch Coxsackievirus B3 im murinen
Tiermodell.
Degree: 2014, Freie Universität Berlin
URL: http://dx.doi.org/10.17169/refubium-4588
► In der hier vorliegenden Arbeit wurde die Rolle des Pathogen-Recognition Rezeptors (PPR) Nod2 in der murinen Myokarditis zum ersten Mal beschrieben. Zu diesem Zweck wurden…
(more)
▼ In der hier vorliegenden Arbeit wurde die Rolle des Pathogen-Recognition
Rezeptors (PPR)
Nod2 in der murinen Myokarditis zum ersten Mal beschrieben. Zu
diesem Zweck wurden
Nod2 Knockout (
Nod2-/-) Mäuse und Wildtyp (WT) Mäuse mit
dem Coxsackie Virus B3 (CVB3) infiziert. Sieben Tage nach Infektion erfolgten
die hämodynamische Charakterisierung der Herzfunktion, mittels
Konduktanzkatheter, und die Entnahme des Herzens für immunhistochemische und
molekularbiologische Untersuchungen. Die Analyse der gewonnenen Druck-Volumen-
Kurven zeigte, dass die Verringerung der globalen, systolischen und
diastolischen Funktion nach CVB3-Infektion bei den
Nod2-/ – Mäusen, verglichen
mit den WT Mäusen, weniger stark ausgeprägt war. Ergänzend dazu, konnte eine
schwächere Entzündungsreaktion im Myokard der
Nod2-/ – CVB3 Mäuse im Vergleich
zu den WT-CVB3 Mäusen detektiert werden. Dies spiegelte sich in einer
geringeren Infiltration von Makrophagen, T- und B-Zellen, sowie einer
geringeren mRNA-Expression von TNF-α und IL-1β wieder. Des Weiteren war die
MCP-1 mRNA-Expression in
Nod2-/ – CVB3 Mäusen im Gegensatz zu den WT-CVB3
Mäusen reduziert, was in der verringerten kardialen Infiltration von
Immunzellen begründet sein könnte. Auch manifestierte sich in
Nod2-/ – CVB3
Mäusen weniger Herzfibrose, assoziiert mit einer verminderten Expression an
Kollagen I, III und α-SMA, weniger kardiale Apoptose und eine reduzierte
Viruslast. Insgesamt deuten diese Ergebnisse auf eine zentrale Rolle von
Nod2
in der Pathogenese der CVB3 induzierten Myokarditis hin. Über die Aktivierung
des NF-κB Signalweges durch
Nod2 wird die kardiale Expression von Zytokinen
und Chemokinen, wie TNF-α, IL-1β und MCP-1, induziert. Dies führt zu einer
Infiltration von Immunzellen in das Herz, weiterhin zur Fibrose, Apoptose und
zu einer erhöhten Viruslast.
Advisors/Committee Members: m (gender), N.N. (firstReferee), N.N. (furtherReferee).
Subjects/Keywords: myocarditis; NOD2; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Xia, Y. (2014). Einfluss der nucleotide-binding Oligomerisation domain-containing protein 2
(Nod 2) auf die virale Myokarditis durch Coxsackievirus B3 im murinen
Tiermodell. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-4588
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Xia, Yu. “Einfluss der nucleotide-binding Oligomerisation domain-containing protein 2
(Nod 2) auf die virale Myokarditis durch Coxsackievirus B3 im murinen
Tiermodell.” 2014. Thesis, Freie Universität Berlin. Accessed March 09, 2021.
http://dx.doi.org/10.17169/refubium-4588.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Xia, Yu. “Einfluss der nucleotide-binding Oligomerisation domain-containing protein 2
(Nod 2) auf die virale Myokarditis durch Coxsackievirus B3 im murinen
Tiermodell.” 2014. Web. 09 Mar 2021.
Vancouver:
Xia Y. Einfluss der nucleotide-binding Oligomerisation domain-containing protein 2
(Nod 2) auf die virale Myokarditis durch Coxsackievirus B3 im murinen
Tiermodell. [Internet] [Thesis]. Freie Universität Berlin; 2014. [cited 2021 Mar 09].
Available from: http://dx.doi.org/10.17169/refubium-4588.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Xia Y. Einfluss der nucleotide-binding Oligomerisation domain-containing protein 2
(Nod 2) auf die virale Myokarditis durch Coxsackievirus B3 im murinen
Tiermodell. [Thesis]. Freie Universität Berlin; 2014. Available from: http://dx.doi.org/10.17169/refubium-4588
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Manchester
9.
Bowcutt, Rowann.
Dendritic cells as a biomarker for gut pathology.
Degree: PhD, 2012, University of Manchester
URL: https://www.research.manchester.ac.uk/portal/en/theses/dendritic-cells-as-a-biomarker-for-gut-pathology(33ff2fed-3955-4401-bd01-6df1f8397642).html
;
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555576
► Trichuris trichiura (T. Trichiura) is a large-intestinal dwelling nematode that affects over 1 billion people world-wide and thus has large global significance. Much of our…
(more)
▼ Trichuris trichiura (T. Trichiura) is a large-intestinal dwelling nematode that affects over 1 billion people world-wide and thus has large global significance. Much of our understanding of T. trichiura infection comes from the study of the mouse model Trichuris muris (T. muris). However, how the immune system is initiated in response to helminth threat and how inflammation and pathology are resolved in T. muris infection still remain to be addressed. Here, I have attempted to provide insight into these questions. Previous work has shown resistance to T. muris infection is associated with the rapid recruitment of dendritic cells (DCs) to the colonic epithelium via epithelial production of CCL5 and CCL20. However, the epithelial-parasite interaction that drives chemokine production is not known. Pattern recognition receptor (PRRS) are critical mediators of pathogen recognition but there is no known (PRR) specific for T. muris. Here, we address the role of the cytosolic pattern recognition receptor Nod2, the location of which within the crypts correlates with the T. muris niche. In WT mice, in response to infection, there was a rapid influx of CD103+CD11c+ DCs into the colonic epithelium, whereas, this recruitment was impaired in Nod2 /- animals. In vitro and in vivo experiments confirmed the impairment in DC recruitment in Nod2-/- mice was attributable to the epithelial compartment. Subsequent work revealed decreased production of epithelial chemokines in the absence of functional Nod2. Thus, we have shown a novel role for Nod2 in the initiation the immune response to T. muris. We next addressed how pathology is regulated during T. muris infection. Firstly we investigated the role of arginase and Arg1-expressing macrophages in regulating pathology. My data showed that, unlike other gastrointestinal helminths, arginase and Arg1-expressing macrophages are not essential for resistance to T. muris or effective resolution of helminth-induced inflammation. I also addressed the role of DCs in the resolution of infection. DCs can regulate immune responses via the anti-inflammatory cytokine IL-10 and induction of regulatory T cells (Treg). I used an IL 10flox/floxCD11cCre transgenic model in which mice have DCs that cannot make IL-10. I found no role for CD11c+ cell mediated IL-10 production in the regulation of pathogen induced pathology in chronic T. muris infection. In summary I have been able to identify factors in the initiation of immunity to T. muris namely epithelial expression of Nod2. However, as arginase, Arg1-expressing macrophages and DC derived IL-10 appeared to play a redundant role in T. muris infection, the question as to how infection induced inflammation is resolved remains elusive.
Subjects/Keywords: 616.9; Dendritic Cell; Nod2; Macrophage; Arginase; Trichuris muris
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APA (6th Edition):
Bowcutt, R. (2012). Dendritic cells as a biomarker for gut pathology. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/dendritic-cells-as-a-biomarker-for-gut-pathology(33ff2fed-3955-4401-bd01-6df1f8397642).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555576
Chicago Manual of Style (16th Edition):
Bowcutt, Rowann. “Dendritic cells as a biomarker for gut pathology.” 2012. Doctoral Dissertation, University of Manchester. Accessed March 09, 2021.
https://www.research.manchester.ac.uk/portal/en/theses/dendritic-cells-as-a-biomarker-for-gut-pathology(33ff2fed-3955-4401-bd01-6df1f8397642).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555576.
MLA Handbook (7th Edition):
Bowcutt, Rowann. “Dendritic cells as a biomarker for gut pathology.” 2012. Web. 09 Mar 2021.
Vancouver:
Bowcutt R. Dendritic cells as a biomarker for gut pathology. [Internet] [Doctoral dissertation]. University of Manchester; 2012. [cited 2021 Mar 09].
Available from: https://www.research.manchester.ac.uk/portal/en/theses/dendritic-cells-as-a-biomarker-for-gut-pathology(33ff2fed-3955-4401-bd01-6df1f8397642).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555576.
Council of Science Editors:
Bowcutt R. Dendritic cells as a biomarker for gut pathology. [Doctoral Dissertation]. University of Manchester; 2012. Available from: https://www.research.manchester.ac.uk/portal/en/theses/dendritic-cells-as-a-biomarker-for-gut-pathology(33ff2fed-3955-4401-bd01-6df1f8397642).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555576
University of Edinburgh
10.
Sharma, Nidhi.
Characterising the role of TLE1 in Crohn's disease.
Degree: PhD, 2016, University of Edinburgh
URL: http://hdl.handle.net/1842/22970
► The inflammatory bowel diseases (IBD) are chronic, relapsing and remitting diseases of the gastrointestinal tract. There are two main types of IBD: Crohn’s disease (CD)…
(more)
▼ The inflammatory bowel diseases (IBD) are chronic, relapsing and remitting diseases of the gastrointestinal tract. There are two main types of IBD: Crohn’s disease (CD) and ulcerative colitis (UC). The prevalence of IBD is highest in the western world, approximately 100-200 people per 100,000 are affected. In recent years there has been a marked increase in the incidence of CD and UC, in both adults and children (Henderson et al., 2012; Molodecky et al., 2012). This is particularly relevant in Scotland where recent research shows that there has been a 79% increase in the number of cases of paediatric IBD since the 1990’s (Henderson et al., 2012). A yeast 2 hybrid screen identified TLE1as an interacting partner of the known CD susceptibility gene; Nucleotide- binding oligomerisation protein 2 (Nod2). An initial genome wide association study (GWAS) also found an association between the rs6559629 SNP, located in Tle1 and ileal CD (p =3.1 x 10-5) and showed that carriage of the Tle1 risk allele increases the effects of Nod2 mutations in CD. TLE1 functions as a transcriptional co repressor in a variety of different cellular and developmental pathways The work presented in this thesis investigates the potential role of TLE1 in CD. This has been approached using four different strategies: sequencing TLE1 in CD patients and controls, analysing the effects of knocking down TLE1 on genome wide expression, investigating whether the known IBD susceptibility protein XBP1 binds to a predicted binding site in TLE1 and investigating TLE1 levels and localisation in human intestinal samples from CD patients and controls Sequencing TLE1 exons and introns 15/16 and 16/17 in a Scottish cohort of 24 CD patients and healthy controls identified a number of potentially pathogenic exonic and intronic SNPs. Two exonic SNPs and thirteen intronic SNPs were identified and these were further investigated in larger Scottish (203 CD cases, 190 HC) and European cohorts (6,333 CD cases and 15,056 HC) but were not present at statistically significantly different frequencies. Secondly, the effects of TLE1 knock down on genome wide expression were analysed using an Illumina HT12 expression chip. The results showed that TLE1 knock down significantly altered expression of 19 loci (Bonferroni) and 526 loci (FDR). Four of the 19 Bonferroni significant loci are potentially involved in CD: RIOK1 (p=4.3×10-3), SGPL1 (p=4.3×10-3), TUSC3 (p=1.8×10-2) and CCND1 (p=2.7×10-3). Furthermore, expression of SGPL1 and RIOK1 were shown to be differentially expressed at the mRNA level between inflamed patients and controls. The third approach investigates a predicted binding site for the known IBD susceptibility gene, XBP1 in TLE1 which was identified using the Haploreg program. This work shows, using chromatin immunoprecipitation, that exogenous XBP1 does not appear to bind to this predicted binding site. Finally, TLE1 expression was analysed in human intestinal resection samples from patients of known NOD2 status. This work shows that TLE1 and NOD2 are expressed in…
Subjects/Keywords: 616.3; Crohn’s disease; TLE1; chromatin immunoprecipitation; NOD2; IBD pathogenesis
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APA (6th Edition):
Sharma, N. (2016). Characterising the role of TLE1 in Crohn's disease. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/22970
Chicago Manual of Style (16th Edition):
Sharma, Nidhi. “Characterising the role of TLE1 in Crohn's disease.” 2016. Doctoral Dissertation, University of Edinburgh. Accessed March 09, 2021.
http://hdl.handle.net/1842/22970.
MLA Handbook (7th Edition):
Sharma, Nidhi. “Characterising the role of TLE1 in Crohn's disease.” 2016. Web. 09 Mar 2021.
Vancouver:
Sharma N. Characterising the role of TLE1 in Crohn's disease. [Internet] [Doctoral dissertation]. University of Edinburgh; 2016. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/1842/22970.
Council of Science Editors:
Sharma N. Characterising the role of TLE1 in Crohn's disease. [Doctoral Dissertation]. University of Edinburgh; 2016. Available from: http://hdl.handle.net/1842/22970
11.
Marinis, Jill M.
Negative Regulation of NOD2 Signaling.
Degree: PhD, Pathology, 2012, Case Western Reserve University School of Graduate Studies
URL: http://rave.ohiolink.edu/etdc/view?acc_num=case1333588972
► The Crohn’s disease susceptibility protein, NOD2, coordinates signaling responses upon intracellular exposure to bacteria. Because dysregulation of this coordination can lead to inflammatory disease,…
(more)
▼ The Crohn’s disease susceptibility protein,
NOD2, coordinates signaling responses upon intracellular exposure
to bacteria. Because dysregulation of this coordination can lead to
inflammatory disease, maintaining appropriate activation of the
NOD2 signaling pathway is paramount in immunologic homeostasis.
Although
NOD2 is known to activate NF-κB, little
is known about the molecular mechanisms by which
NOD2 coordinates
functionally separate signaling pathways such as NF-κB, JNK, and
p38 to regulate cytokine responses, or the mechanisms by which
NOD2
signaling is terminated. Given that one of the characteristics of
Crohn’s disease is an altered cytokine response to normal bacterial
flora, the coupling and termination of signaling pathways is likely
to be important for Crohn’s-disease pathophysiology.Coordination of
NOD2 induced NF-κB and MAPK signaling is achieved in part at the
level of the MAP3K’s. We identify the MAP3K, MEKK4, as a binding
partner of RIP2. This MEKK4:RIP2 complex dissociates upon exposure
to the
NOD2 agonist, MDP, allowing
NOD2 to bind to RIP2 and
activate NF-κB. MEKK4 thus sequesters RIP2 to inhibit the
NOD2:RIP2
complex from activating NF-κB signaling pathways. MEKK4 also helps
dictate signal specificity downstream of
NOD2 activation as
knockdown of MEKK4 causes increased NF-κB activity, absent p38
activity, and hypo-responsiveness to TLR2 and TLR4 agonists. TRAF
proteins are involved in several inflammatory signaling networks.
We identify the atypical TRAF family member, TRAF4, as a key
negative regulator of
NOD2 signaling. TRAF4 inhibits
NOD2-induced
NF-κB activation and directly binds to
NOD2 to inhibit
NOD2-induced
bacterial killing. We find that two consecutive glutamate residues
in
NOD2 are required for interaction with TRAF4 and inhibition of
NOD2 signaling. Finally, we find that IKKα
phosphorylates TRAF4 at S426 to enhance its function as a negative
regulator of
NOD2 signaling. Phosphorylation of this site affects
TRAF4’s ability to bind
NOD2, and allows it to inhibit
NOD2
signaling. Structurally, Serine-426 resides within an exaggerated
β-bulge in TRAF4 that is not present in the other TRAF proteins,
and phosphorylation of this site provides a structural basis for
the atypical function of TRAF4 and its atypical role in
NOD2
signaling.
Advisors/Committee Members: Dubyak, George (Committee Chair), Abbott, Derek (Advisor).
Subjects/Keywords: Biomedical Research; Immunology; Innate Immunity; NOD2; TRAF4; IKKalpha
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APA ·
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Manager
APA (6th Edition):
Marinis, J. M. (2012). Negative Regulation of NOD2 Signaling. (Doctoral Dissertation). Case Western Reserve University School of Graduate Studies. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=case1333588972
Chicago Manual of Style (16th Edition):
Marinis, Jill M. “Negative Regulation of NOD2 Signaling.” 2012. Doctoral Dissertation, Case Western Reserve University School of Graduate Studies. Accessed March 09, 2021.
http://rave.ohiolink.edu/etdc/view?acc_num=case1333588972.
MLA Handbook (7th Edition):
Marinis, Jill M. “Negative Regulation of NOD2 Signaling.” 2012. Web. 09 Mar 2021.
Vancouver:
Marinis JM. Negative Regulation of NOD2 Signaling. [Internet] [Doctoral dissertation]. Case Western Reserve University School of Graduate Studies; 2012. [cited 2021 Mar 09].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1333588972.
Council of Science Editors:
Marinis JM. Negative Regulation of NOD2 Signaling. [Doctoral Dissertation]. Case Western Reserve University School of Graduate Studies; 2012. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1333588972
12.
Costa, Frederico Ribeiro Campos.
A ativação do receptor NOD2 contribui para a imunopatogenia do diabetes tipo 1 experimental.
Degree: Mestrado, Imunologia Básica e Aplicada, 2014, University of São Paulo
URL: http://www.teses.usp.br/teses/disponiveis/17/17147/tde-18032014-150659/
;
► Diabetes tipo 1 (DM1) e uma doenca autoimune que se inicia devido a defeitos na tolerancia imunologica a auto-antigenos, resultando na destruicao autoimune das celulas…
(more)
▼ Diabetes tipo 1 (DM1) e uma doenca autoimune que se inicia devido a defeitos na tolerancia imunologica a auto-antigenos, resultando na destruicao autoimune das celulas pancreaticas em individuos geneticamente suscetiveis. Os receptores NOD-like (NLRs) sao receptores intracelulares responsaveis pelo reconhecimento de padroes moleculares associados a patogenos (PAMPs) e padroes moleculares associados ao dano (DAMPs). Estudos recentes tem demonstrado que os receptores NOD1 e NOD2 desempenham um importante papel na ativacao da imunidade inata contra patogenos e na regulacao da imunidade adaptativa, uma vez que sua ativacao leva a producao de citocinas relacionadas a diferenciacao de linfocitos T auxiliares produtores de IL-17 (Th17). Porem, a importancia desses receptores no DM1 ainda e incerto. Nesse sentido, investigamos o papel dos receptores NOD1 e NOD2 na patogenese do DM1, com enfoque na diferenciacao de linfocitos Treg/Th17/Th1 e na plasticidade desses subtipos celulares. Nossos resultados mostram que camundongos deficientes de NOD2, mas nao NOD1 ou RIP2, sao resistentes ao DM1, como comprovado por menor incidencia, hiperglicemia, diminuicao do infiltrado inflamatorio e normalizacao dos niveis de insulina quando comparado aos controles. Foi observado tambem que animais NOD2-/- tiveram uma reducao da populacao de linfocitos Th17, Tc17, Th1 e T citotoxicos nos linfonodos pancreaticos, o que correlaciona com a inibicao da producao de IL-23p19 e IFN- no pancreas. Em paralelo, foi evidenciado o aumento do numero de celulas T reguladoras, macrofagos do perfil M2 nos linfonodos pancreaticos e elevada producao de IL-10 no pancreas de animais NOD2-/-. Alem disso, foi observado que animais NOD2-/- apresentaram uma menor populacao de linfocitos T duplo-positivos (Foxp3+RORt+ e IL-17+IFN+). Posteriormente, foi detectado menor producao de IL- 1, IL-6, IL-23p19 e IL-12p40 por celulas dendriticas de animais deficientes de NOD2. De forma interessante, foi observada a translocacao de bacterias para os linfonodos pancreaticos de animais diabeticos. Adicionalmente, animais tratados com antibioticos tornaram-se resistentes ao DM1, o que nos fornece indicios da contribuicao da microbiota intestinal na inducao da doenca. Por fim, comprovamos alta expressao genica de NOD2 nos linfonodos pancreaticos e no pancreas na fase inicial (pre-diabetica) em outro modelo de DM1, utilizando camundongos NOD (nonobese diabetic mice). Portanto, nossos dados indicam que a ativacao do receptor NOD2 por componentes bacterianos da microbiota intestinal induz a producao de citocinas pro-inflamatorias com subsequente diferenciacao/conversao de linfocitos do perfil Th17/Th1 e progressao do DM1. Dessa forma, estes dados apontam o bloqueio do receptor NOD2 como uma potencial terapia imunomoduladora para o DM1 em humanos.
Type 1 diabetes is an autoimmune disease that precipitates due to defects in the self tolerance to auto- antigens, resulting in the autoimmune destruction of the pancreatic cells in genetically susceptible individuals. NOD-like (NLRs)…
Advisors/Committee Members: Sartori, Daniela Carlos.
Subjects/Keywords: Balanco Treg/Th17/Th1; Diabetes tipo 1; Gut Microbiota; M1 and M2 macrophages; Macrofagos M1 e M2; Microbiota; NOD2; NOD2; Treg/Th1/Th17 balance; Type 1 Diabetes
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APA ·
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MLA ·
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Export
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Manager
APA (6th Edition):
Costa, F. R. C. (2014). A ativação do receptor NOD2 contribui para a imunopatogenia do diabetes tipo 1 experimental. (Masters Thesis). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/17/17147/tde-18032014-150659/ ;
Chicago Manual of Style (16th Edition):
Costa, Frederico Ribeiro Campos. “A ativação do receptor NOD2 contribui para a imunopatogenia do diabetes tipo 1 experimental.” 2014. Masters Thesis, University of São Paulo. Accessed March 09, 2021.
http://www.teses.usp.br/teses/disponiveis/17/17147/tde-18032014-150659/ ;.
MLA Handbook (7th Edition):
Costa, Frederico Ribeiro Campos. “A ativação do receptor NOD2 contribui para a imunopatogenia do diabetes tipo 1 experimental.” 2014. Web. 09 Mar 2021.
Vancouver:
Costa FRC. A ativação do receptor NOD2 contribui para a imunopatogenia do diabetes tipo 1 experimental. [Internet] [Masters thesis]. University of São Paulo; 2014. [cited 2021 Mar 09].
Available from: http://www.teses.usp.br/teses/disponiveis/17/17147/tde-18032014-150659/ ;.
Council of Science Editors:
Costa FRC. A ativação do receptor NOD2 contribui para a imunopatogenia do diabetes tipo 1 experimental. [Masters Thesis]. University of São Paulo; 2014. Available from: http://www.teses.usp.br/teses/disponiveis/17/17147/tde-18032014-150659/ ;
13.
Levy, Antonin.
Impact of microbiota on intestinal stem cells survival after irradiation : Impact de la flore microbienne dans la survie des cellules souches intestinales après irradiation.
Degree: Docteur es, Sciences de la vie et de la santé, 2018, Sorbonne Paris Cité
URL: http://www.theses.fr/2018USPCC321
► L'épithélium intestinal est un tissu à renouvellement rapide impliquant l’activité de cellules souches intestinales (CSIs) identifiées par le marqueur LGR5. L'épithélium intestinal doit faire face…
(more)
▼ L'épithélium intestinal est un tissu à renouvellement rapide impliquant l’activité de cellules souches intestinales (CSIs) identifiées par le marqueur LGR5. L'épithélium intestinal doit faire face à des agressions continues en relation avec ses fonctions digestives et de barrière. Le microbiote intestinal, y compris les agents pathogènes et les bactéries commensales, influence l'intégrité et la physiologie de l'épithélium intestinal. L'interaction des molécules dérivées du microbiote avec les récepteurs immunitaires innés de l'hôte est nécessaire à l'homéostasie intestinale et son rôle est encore plus important dans des conditions de stress, en particulier celles induisant un fort stress oxydatif. Les CSIs LGR5+ expriment le récepteur immunitaire inné cytosolique
NOD2. Le ligand de
NOD2, le muramyl-dipeptide (MDP), un motif du peptidoglycane commun à toutes les bactéries, favorise la survie des CSIs suite à un stress oxydatif, autrement mortel. Cependant, les mécanismes de protection sous-jacents demeurent encore inconnus.L'exposition de souris axéniques ou conventionnelles aux rayonnements ionisants conduit à différents résultats. Cependant, les mécanismes conférant la radiorésistance des souris axéniques sont mal compris. Des données préliminaires de notre groupe ont indiqué que les CSIs axéniques sont résistantes aux dommages induits par la chimiothérapie, suggérant que le microbiote pourrait être impliqué dans l'initiation de la sensibilité des CSIs aux agents générant un stress oxydatif.Afin de caractériser l'interaction microbiote-CSIs après irradiation ionisante, nous avons utilisé des modèles murins in vivo et in vitro (culture d’organoïde intestinaux).Nous avons constaté qu’après irradiation in vitro (i) la transcription de
Nod2 était augmentée dans les CSIs et (ii) que le MDP favorisait spécifiquement la protection des CSIs. Nous avons ensuite montré que l'addition du MDP induisait une forte diminution des espèces réactives de l’oxygène (ROS) totales et mitochondriales au sein des CSIs après irradiation. Les CSIs LGR5+ présentent une activité mitochondriale élevée et les mitochondries sont une source majeure de ROS. Nous avons démontré que la mitophagie intrinsèque aux CSIs, un mécanisme important pour l’homéostasie, est activée par le MDP, ce qui suggère un rôle pour son récepteur
NOD2. De plus, les organoïdes dépourvus d’une protéine impliquée dans l’autophagie (ATG16L1 KO) ne bénéficiaient pas de la protection du MDP après irradiation in vitro. La cytoprotection médiée par le MDP a cependant pu être restaurée dans le contexte ATG16L1 KO en ajoutant un agent antioxydant. Nous avons également confirmé des défauts dans le processus de mitophagie chez les organoides de souris
NOD2 KO. Ces résultats permettent une meilleure compréhension des mécanismes de cytoprotection induits par le MDP et soulignent les liens entre
NOD2 et autophagie.Nous avons également démontré la radiorésistance relative des cryptes des souris axéniques, comparativement aux souris témoins in vivo. De plus, les organoides de souris…
Advisors/Committee Members: Sansonetti, Philippe (thesis director), Deutsch, Eric (thesis director).
Subjects/Keywords: Cellules souches intestinales; Microbiote; Irradiation; Protéine adaptatrice de signalisation NOD2; Muramyl-dipeptide; Intestinal stem cells; Microbiota; Exposure, radiation; Nod2 signaling adaptor protein; Muramyl-dipeptide
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APA (6th Edition):
Levy, A. (2018). Impact of microbiota on intestinal stem cells survival after irradiation : Impact de la flore microbienne dans la survie des cellules souches intestinales après irradiation. (Doctoral Dissertation). Sorbonne Paris Cité. Retrieved from http://www.theses.fr/2018USPCC321
Chicago Manual of Style (16th Edition):
Levy, Antonin. “Impact of microbiota on intestinal stem cells survival after irradiation : Impact de la flore microbienne dans la survie des cellules souches intestinales après irradiation.” 2018. Doctoral Dissertation, Sorbonne Paris Cité. Accessed March 09, 2021.
http://www.theses.fr/2018USPCC321.
MLA Handbook (7th Edition):
Levy, Antonin. “Impact of microbiota on intestinal stem cells survival after irradiation : Impact de la flore microbienne dans la survie des cellules souches intestinales après irradiation.” 2018. Web. 09 Mar 2021.
Vancouver:
Levy A. Impact of microbiota on intestinal stem cells survival after irradiation : Impact de la flore microbienne dans la survie des cellules souches intestinales après irradiation. [Internet] [Doctoral dissertation]. Sorbonne Paris Cité; 2018. [cited 2021 Mar 09].
Available from: http://www.theses.fr/2018USPCC321.
Council of Science Editors:
Levy A. Impact of microbiota on intestinal stem cells survival after irradiation : Impact de la flore microbienne dans la survie des cellules souches intestinales après irradiation. [Doctoral Dissertation]. Sorbonne Paris Cité; 2018. Available from: http://www.theses.fr/2018USPCC321
North Carolina State University
14.
Kim, Jae-Young.
TAK1 is a Central Mediator of NOD2 Signaling and is Essential for Intestinal Epithelial Cell Protection against Chemical-induced Colitis.
Degree: PhD, Toxicology, 2009, North Carolina State University
URL: http://www.lib.ncsu.edu/resolver/1840.16/5847
► Innate immunity is the first line of defense against invasive microbial pathogens. It is triggered by several families of pattern-recognition receptors (PRRs), which activate cellular…
(more)
▼ Innate immunity is the first line of defense against invasive microbial pathogens. It is triggered by several families of pattern-recognition receptors (PRRs), which activate cellular responses including activation of NF-κB and mitogen-activated protein kinases (MAPKs) signaling, and subsequently the induction of proinflammatory genes. There are two groups of PRRs, toll-like receptors (TLRs) and nod-like receptors (NLRs). In contrast to TLRs that recognize microbes via plasma membrane or endosomal receptors, NLRs induce innate immune response by detecting bacterial components released into the cytosol. Nucleotide oligomerization domain 2 (
NOD2) is the best characterized member of the NLR family. Upon
NOD2 stimulation by muramyl dipeptide (MDP), a
NOD2-specific ligand originating from the bacterial cell wall, it associates with an adaptor molecule, RIP-like interacting CLARP kinase (RICK, also called Rip2) and activates both NF-κB and MAPKs signaling pathways, which lead to inflammatory gene expression. However, the molecular mechanism by which
NOD2-RICK complex activates its downstream signals remains elusive. Here, we report that TGF β-activated kinase 1 (TAK1) is a central mediator of
NOD2 signaling in epidermal cells. TAK1 belongs to MAPKKK family and plays an essential role in activating NF-κB and MAPKs signaling in tumor necrosis factor (TNF), interleukin-1 (IL-1), and TLR signaling pathways. In this study, we found that MDP-induced proinflammatory gene expression as well as the activation of
NOD2 downstream signals including NF-κB, c-Jun N-terminal kinase (JNK) and p38 were completely abolished in TAK1-deficient keratinocytes, indicating that TAK1 is essential for eliciting
NOD2-induced innate immune responses.
NOD2 and its downstream adaptor, RICK, associated with and activated TAK1. Endogenous TAK1-RICK interaction was enhanced by MDP, suggesting that
NOD2-RICK-TAK1 complex is induced in an MDP-dependent manner.
We have previously reported that intestinal epithelium-specific TAK1 deletion mice showed severe inflammation and mortality at postnatal day 1 due to TNF-induced epithelial cell death. In this study, we investigated TNF-independent role of TAK1 by utilizing mice harboring double deletion of TNF receptor 1 (TNFR1) and intestinal epithelium-specific deletion of TAK1 (TNFR1KO/TAK1IEKO). To study the role of TAK1 in the intestinal epithelial barrier, the mice were subjected to acute colitis by administration of dextran sulfate sodium (DSS). We found that loss of TAK1 significantly augments DSS-induced experimental colitis. DSS-induced weight loss, intestinal damage and inflammatory markers were significantly increased in TNFR1KO/TAK1IEKO mice compared to the TNFR1KO control mice. Following DSS exposure, apoptosis was strongly induced and epithelial cell proliferation was decreased in the TAK1-deficient intestinal epithelium. These results suggest that epithelial-derived TAK1 signaling is important for cytoprotection and tissue repair after injury. Finally, we showed that TAK1 is essential…
Advisors/Committee Members: Robert C. Smart, Committee Member (advisor), Yoshiaki Tsuji, Committee Member (advisor), Jun Ninomiya-Tsuji, Committee Chair (advisor), Christian Jobin, Committee Member (advisor).
Subjects/Keywords: intestine; autophagy; aging; TAK1; NOD2; Crohn’s disease; inflammation; MAPK; NF-kB
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APA ·
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APA (6th Edition):
Kim, J. (2009). TAK1 is a Central Mediator of NOD2 Signaling and is Essential for Intestinal Epithelial Cell Protection against Chemical-induced Colitis. (Doctoral Dissertation). North Carolina State University. Retrieved from http://www.lib.ncsu.edu/resolver/1840.16/5847
Chicago Manual of Style (16th Edition):
Kim, Jae-Young. “TAK1 is a Central Mediator of NOD2 Signaling and is Essential for Intestinal Epithelial Cell Protection against Chemical-induced Colitis.” 2009. Doctoral Dissertation, North Carolina State University. Accessed March 09, 2021.
http://www.lib.ncsu.edu/resolver/1840.16/5847.
MLA Handbook (7th Edition):
Kim, Jae-Young. “TAK1 is a Central Mediator of NOD2 Signaling and is Essential for Intestinal Epithelial Cell Protection against Chemical-induced Colitis.” 2009. Web. 09 Mar 2021.
Vancouver:
Kim J. TAK1 is a Central Mediator of NOD2 Signaling and is Essential for Intestinal Epithelial Cell Protection against Chemical-induced Colitis. [Internet] [Doctoral dissertation]. North Carolina State University; 2009. [cited 2021 Mar 09].
Available from: http://www.lib.ncsu.edu/resolver/1840.16/5847.
Council of Science Editors:
Kim J. TAK1 is a Central Mediator of NOD2 Signaling and is Essential for Intestinal Epithelial Cell Protection against Chemical-induced Colitis. [Doctoral Dissertation]. North Carolina State University; 2009. Available from: http://www.lib.ncsu.edu/resolver/1840.16/5847
University of Delaware
15.
Hou, Ching-Wen.
The sweet modification of Nod2, an innate immune receptor involved in Crohn's disease.
Degree: PhD, University of Delaware, Department of Chemistry and Biochemistry, 2017, University of Delaware
URL: http://udspace.udel.edu/handle/19716/23031
► The innate immune system, the first line of defense against pathogens, utilizes a series of receptors, including Toll-like receptors and Nod-like receptors, to generate the…
(more)
▼ The innate immune system, the first line of defense against pathogens, utilizes a series of receptors, including Toll-like receptors and Nod-like receptors, to generate the proper immune response. ☐ Nucleotide-binding oligomerization domain 2 (
Nod2) is one of Nod-like receptors that can sense the bacterial peptidoglycan component, muramyl dipeptide (MDP). Upon activation
Nod2 induces the production of various inflammatory molecules such as cytokines and chemokines. Genetic linkage analysis identified and revealed three major mutations in
Nod2 associated with the development of Crohn’s disease are R702W, G908R, and 1007fs. In addition, previous studies have shown these
Nod2 variants have lower NF-kB activation in response to MDP compared to wild type
Nod2. ☐ The objective of this dissertation is to further characterize
Nod2 and determine if it is post-translationally modified by O-GlcNAc. O-GlcNAcylation is one type of post-translational modification in which the O-GlcNAc transferase (OGT) transfers N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to selected serine and threonine residues of intracellular proteins. As GlcNAc is a major component of peptidoglycan of the bacterial cell wall and a large amount of GlcNAc is released from bacterial cell wall during cell wall remodeling, we hypothesized that
Nod2 could be O-GlcNAcylated. ☐ We found that wild type
Nod2 and
Nod2 Crohn’s-associated variants are O- GlcNAcylated. This modification affects both wild type and Crohn’s mutant’s Nod2’s stability and ability to signal via the NF-κB pathway. ☐ Finally, in order to identify the peptidoglycan fragments that are generated inside the cellular environment, we have developed a new labelling approach to study peptidoglycan degradation process in vivo. Ultimately, we will utilize this approach to identify peptidoglycan fragments that effect the level of O-GlcNAcylation and OGT activity.
Advisors/Committee Members: Grimes, Catherine Leimkuhler.
Subjects/Keywords: Pure sciences; Crohn's disease; NF-kB activity; Nod2; O-GlcNAcylation; Protein stability
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Manager
APA (6th Edition):
Hou, C. (2017). The sweet modification of Nod2, an innate immune receptor involved in Crohn's disease. (Doctoral Dissertation). University of Delaware. Retrieved from http://udspace.udel.edu/handle/19716/23031
Chicago Manual of Style (16th Edition):
Hou, Ching-Wen. “The sweet modification of Nod2, an innate immune receptor involved in Crohn's disease.” 2017. Doctoral Dissertation, University of Delaware. Accessed March 09, 2021.
http://udspace.udel.edu/handle/19716/23031.
MLA Handbook (7th Edition):
Hou, Ching-Wen. “The sweet modification of Nod2, an innate immune receptor involved in Crohn's disease.” 2017. Web. 09 Mar 2021.
Vancouver:
Hou C. The sweet modification of Nod2, an innate immune receptor involved in Crohn's disease. [Internet] [Doctoral dissertation]. University of Delaware; 2017. [cited 2021 Mar 09].
Available from: http://udspace.udel.edu/handle/19716/23031.
Council of Science Editors:
Hou C. The sweet modification of Nod2, an innate immune receptor involved in Crohn's disease. [Doctoral Dissertation]. University of Delaware; 2017. Available from: http://udspace.udel.edu/handle/19716/23031
Freie Universität Berlin
16.
Grundmann, Ursula.
The role of NOD2 in the Campylobacter jejuni-induced colitis in a gnotobiotic
mouse model.
Degree: 2015, Freie Universität Berlin
URL: http://dx.doi.org/10.17169/refubium-6853
► Introduction: The cytosolic pattern recognition receptor NOD2 modulates responses of the in-nate and the adaptive immune systems. Mutations of NOD2 are significantly associated with Crohn’s…
(more)
▼ Introduction: The cytosolic pattern recognition receptor
NOD2 modulates
responses of the in-nate and the adaptive immune systems. Mutations of
NOD2
are significantly associated with Crohn’s disease, an inflammatory bowel
disease. The Gram-negative bacteria Campylobacter jejuni causes the most
frequent cause of bacterial diarrhea in Europe. Despite its socio-economic
impact adequate models for the investigation of C. jejuni infection and
inflammation are still lacking. The pathogenesis of Campylobacteriosis is
poorly understood. Therefore, functions of
NOD2 were investigated in the novel
gnotobiotic murine C. jejuni infection models. Methods: Gnotobiotic mice
generated by an oral, quintuple antibiotic regime are susceptible to C. jejuni
infection. Three to four months old WT- and
NOD2-/ – mice, and IL-10-/ – and
NOD2-/ – IL-10-/ – mice respectively, were infected with the C. jejuni strain
81-176 perorally. The animals were controlled each day and sacrificed on day
six. Microbiological, histological and immunological analyses were performed
and statistically evaluated. Results: Gnotobiotic WT- and
NOD2-/ – mice were
infected with C. jejuni. The infection caused no symptomatic outcome but it
decreased the expression of
NOD2 in the WT-mice. The infection increased
concentrations of pro- as well as anti-inflammatory cytokines of the innate
and adaptive immune systems (namely TNF-a, MCP-1, IL-6, IL-10, IFN-g, IL-17A
and IL-22).
NOD2 inhibited the production of NO, TNF-a, MCP-1, IL-6 and IL-10
in the intestines. Secondly gnotobiotic IL-10-/ – and
NOD2-/ – IL-10-/ – mice,
infected with C. jejuni, showed a mas-sive ulcerative colitis accompanied by
clinical symptoms and an increase of IL-1-b, NO, TNF-a, IL-6, MCP-1, IFN-g,
IL-17A and IL-22 in the colon. Here too the infection by C. jejuni caused a
decreased expression of
NOD2 in IL-10-/ – mice.
NOD2 aggravated the clinical
outcome of the animals and the histopathology in the colon. Anyway mice
deficient in
NOD2 showed signifi-cantly higher levels of MCP-1, IL-6, IFN-g
and IL-22 as compared to IL-10-/ – control mice. Conclusion: In both murine
models
NOD2 regulates and limits the activation of the immune system by
inhibiting the production of pro- as well as anti-inflammatory cytokines. This
inhibitory function of
NOD2 was already diminished by decrease of the
expression of
NOD2 follow-ing C. jejuni infection. It can be assumed that in
both models a
NOD2 mediated inhibition of Toll-like-receptor signaling was
responsible for the augmented cytokine production in
NOD2-deficient animals.
Inhibition of TLR2-responses by
NOD2 has been already described in earlier
studies. It is already known that TLR2- and TLR4-signaling is essential for C.
jejuni-mediated inflammation in the colon.
Advisors/Committee Members: [email protected] (contact), w (gender), N.N. (firstReferee), N.N. (furtherReferee).
Subjects/Keywords: NOD2; Campylobacter jejuni; gnotobiotic mouse model; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit
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APA (6th Edition):
Grundmann, U. (2015). The role of NOD2 in the Campylobacter jejuni-induced colitis in a gnotobiotic
mouse model. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-6853
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Grundmann, Ursula. “The role of NOD2 in the Campylobacter jejuni-induced colitis in a gnotobiotic
mouse model.” 2015. Thesis, Freie Universität Berlin. Accessed March 09, 2021.
http://dx.doi.org/10.17169/refubium-6853.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Grundmann, Ursula. “The role of NOD2 in the Campylobacter jejuni-induced colitis in a gnotobiotic
mouse model.” 2015. Web. 09 Mar 2021.
Vancouver:
Grundmann U. The role of NOD2 in the Campylobacter jejuni-induced colitis in a gnotobiotic
mouse model. [Internet] [Thesis]. Freie Universität Berlin; 2015. [cited 2021 Mar 09].
Available from: http://dx.doi.org/10.17169/refubium-6853.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Grundmann U. The role of NOD2 in the Campylobacter jejuni-induced colitis in a gnotobiotic
mouse model. [Thesis]. Freie Universität Berlin; 2015. Available from: http://dx.doi.org/10.17169/refubium-6853
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Melbourne
17.
Stafford, Che Alan.
Investigation into the regulatory mechanisms of the NOD2 signalling pathway.
Degree: 2018, University of Melbourne
URL: http://hdl.handle.net/11343/213476
► Nucleotide-binding oligomerisation domain-containing (NOD) receptor 2 (NOD2) is a critical intracellular sentinel for Gram-positive and Gram-negative bacteria through the recognition of the bacterial cell wall…
(more)
▼ Nucleotide-binding oligomerisation domain-containing (NOD) receptor 2 (NOD2) is a critical intracellular sentinel for Gram-positive and Gram-negative bacteria through the recognition of the bacterial cell wall component muramyl dipeptide (MDP). NOD2 signalling relies on the recruitment and ubiquitylation of the adaptor kinase receptor interacting protein kinase 2 (RIPK2). Multiple E3-ubiquitin ligases have been reported as vital components of the NOD2 signalling complex, including X-linked inhibitor of apoptosis (XIAP), and cellular IAP1 and 2 (cIAP1 & cIAP2). All of these E3 ligases have been shown to have the ability to bind and ubiquitylate RIPK2, yet their physiological role in the NOD2 pathway is unclear. Only a few members of the NOD2 signalling complex have been identified and validated under endogenous conditions, due to a lack of molecular tools. Critically, over-expression of signalling components is an imperfect way to analyse this complex, since it leads to the activation of the pathway independent of MDP engagement.
In this thesis, I have identified novel molecular mechanisms of how NOD2 signalling is regulated. Firstly, I clarified that XIAP is the only IAP required for signalling immediately downstream of NOD2, whilst cIAP1 and cIAP2 are dispensable. Through genetic removal of TNFR1 pathway members, I discovered a TNFR1-dependent autocrine amplification loop, following NOD2 activation, which implicates cIAP1 and cIAP2 in the overall cytokine response to MDP.
In the second project, I aimed to better understand how the kinase activity of RIPK2 impacts upon NOD2 signalling. For this, I purified and crystallised the recombinant human RIPK2 kinase domain and observed a potential dimerisation interface which may be critical for signalling. This work has established a structural biology approach that can be used for future development of RIPK2 inhibitors.
Finally, using a combination of cell biology, biochemistry and chemical biology, I developed and optimised a functionalised MDP-ligand that can endogenously pull-down NOD2 complex members, which will be used to identify novel NOD2 interactors.
Together, work from this thesis provides unprecedented clarity surrounding the role of putative E3-ligases in NOD2 signalling, which not only rectified the literature, it will open up many avenues for novel research. This work also establishes the groundwork for structure-led development of future RIPK2 inhibitors, and provides a much-needed endogenous tool to delineate novel interacting partners.
Subjects/Keywords: NOD2; RIPK2; innate immunity; structural biology; cell biology; bacterial recognition; cell signalling; Muramyl Dipeptide
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APA ·
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APA (6th Edition):
Stafford, C. A. (2018). Investigation into the regulatory mechanisms of the NOD2 signalling pathway. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/213476
Chicago Manual of Style (16th Edition):
Stafford, Che Alan. “Investigation into the regulatory mechanisms of the NOD2 signalling pathway.” 2018. Doctoral Dissertation, University of Melbourne. Accessed March 09, 2021.
http://hdl.handle.net/11343/213476.
MLA Handbook (7th Edition):
Stafford, Che Alan. “Investigation into the regulatory mechanisms of the NOD2 signalling pathway.” 2018. Web. 09 Mar 2021.
Vancouver:
Stafford CA. Investigation into the regulatory mechanisms of the NOD2 signalling pathway. [Internet] [Doctoral dissertation]. University of Melbourne; 2018. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/11343/213476.
Council of Science Editors:
Stafford CA. Investigation into the regulatory mechanisms of the NOD2 signalling pathway. [Doctoral Dissertation]. University of Melbourne; 2018. Available from: http://hdl.handle.net/11343/213476
18.
Couturier-Maillard, Aurélie.
Etude des interactions du microbiote intestinal avec le récepteur de l’immunité innée NOD2 dans la maladie de Crohn et le cancer colorectal : Interactions between intestinal microbiota and innate immunity receptor NOD2 in Crohn disease and colorectal cancer.
Degree: Docteur es, Immunologie, 2012, Université Lille II – Droit et Santé
URL: http://www.theses.fr/2012LIL2S008
► Pathologie multifactorielle, la maladie de Crohn pourrait être la conséquence de facteurs environnementaux, génétiques et impliquerait également une dérégulation de la réponse immunitaire vis-à-vis du…
(more)
▼ Pathologie multifactorielle, la maladie de Crohn pourrait être la conséquence de facteurs environnementaux, génétiques et impliquerait également une dérégulation de la réponse immunitaire vis-à-vis du microbiote intestinal. En effet, des variations qualitatives et quantitatives du microbiote intestinal ont pu être mises en évidence chez les patients atteints de cette pathologie. Dysbiose également observée dans le cancer colorectal dont le risque de développement est doublé chez les patients atteints de maladie de Crohn.Dans cette étude, nous nous sommes intéressés au rôle du récepteur de l’immunité innée
NOD2, dont les polymorphismes génétiques prédisposent à la maladie de Crohn ainsi qu’à l’influence du microbiote intestinal dans l’établissement de colites et du cancer colorectal.Un modèle murin de colite chimique et de cancer associé à la colite (CAC) a permis de mettre en évidence une aggravation des signes cliniques de ces pathologies chez les animaux
Nod2-/- et Rip2-/- en comparaison aux animaux sauvages suggérant un rôle protecteur de
NOD2 et de son adaptateur protéique RIP2 dans la colite et à plus long terme dans la tumorigenèse.En vue de déterminer l’origine de ce sur-risque observé chez les animaux
Nod2 ou Rip2-déficients nous avons tout d’abord vérifié le caractère transmissible de la colite. Des expériences de co-hébergement et d’adoption ont montré une transmission de la susceptibilité associée aux animaux déficients à des animaux sauvages de manière horizontale (par les congénères) et verticale (par la mère). Une analyse systématique du microbiote dans le modèle de CAC a mis en évidence une réduction de la diversité microbienne ainsi qu’une dysbiose chez les animaux
Nod2-/- suggérant une implication de la flore dans l’établissement du sur-risque observé chez les animaux déficients. L’administration d’une antibiothérapie à large spectre a conforté cette hypothèse en réduisant la susceptibilité des animaux
Nod2-/-. Une analyse transcriptionnelle a été réalisée afin d’établir les mécanismes moléculaires associés à la colite en réponse au microbiote et a permis de mettre en cause l’IL-6 ainsi que ses gènes cibles déjà décrits pour leur caractère pro-tumoral. Implication confirmée par inhibition de la voie IL-6 à l’aide d’un anticorps bloquant son récepteur capable de réduire la tumorigenèse. Enfin, la génération de souris axéniques
Nod2-/- et leur recolonisation par une flore issue de souris sauvages a montré la possibilité d’inverser le sur-risque observé chez les
Nod2-/-.Pour conclure, dans un contexte déficient pour
Nod2, une réponse inflammatoire à l’encontre du microbiote intestinal dépendante de l’IL-6 favoriserait la mise en place d’une flore délétère qui prédisposerait à la colite et au CAC. Le caractère transmissible de cette flore représente en soi un outil pour l’étude des interactions avec le système immunitaire inné et adaptatif. Enfin, la mise en évidence de la ou des bactéries colitogènes ainsi que des mécanismes inflammatoires impliqués, permettra la mise au point de thérapies ciblées en…
Advisors/Committee Members: Chamaillard, Mathias (thesis director).
Subjects/Keywords: Maladie de Crohn; Cancer du côlon; NOD2; Microflore; Dysbiose; Neoplasms, Colorectal; Crohn's disease
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APA ·
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APA (6th Edition):
Couturier-Maillard, A. (2012). Etude des interactions du microbiote intestinal avec le récepteur de l’immunité innée NOD2 dans la maladie de Crohn et le cancer colorectal : Interactions between intestinal microbiota and innate immunity receptor NOD2 in Crohn disease and colorectal cancer. (Doctoral Dissertation). Université Lille II – Droit et Santé. Retrieved from http://www.theses.fr/2012LIL2S008
Chicago Manual of Style (16th Edition):
Couturier-Maillard, Aurélie. “Etude des interactions du microbiote intestinal avec le récepteur de l’immunité innée NOD2 dans la maladie de Crohn et le cancer colorectal : Interactions between intestinal microbiota and innate immunity receptor NOD2 in Crohn disease and colorectal cancer.” 2012. Doctoral Dissertation, Université Lille II – Droit et Santé. Accessed March 09, 2021.
http://www.theses.fr/2012LIL2S008.
MLA Handbook (7th Edition):
Couturier-Maillard, Aurélie. “Etude des interactions du microbiote intestinal avec le récepteur de l’immunité innée NOD2 dans la maladie de Crohn et le cancer colorectal : Interactions between intestinal microbiota and innate immunity receptor NOD2 in Crohn disease and colorectal cancer.” 2012. Web. 09 Mar 2021.
Vancouver:
Couturier-Maillard A. Etude des interactions du microbiote intestinal avec le récepteur de l’immunité innée NOD2 dans la maladie de Crohn et le cancer colorectal : Interactions between intestinal microbiota and innate immunity receptor NOD2 in Crohn disease and colorectal cancer. [Internet] [Doctoral dissertation]. Université Lille II – Droit et Santé 2012. [cited 2021 Mar 09].
Available from: http://www.theses.fr/2012LIL2S008.
Council of Science Editors:
Couturier-Maillard A. Etude des interactions du microbiote intestinal avec le récepteur de l’immunité innée NOD2 dans la maladie de Crohn et le cancer colorectal : Interactions between intestinal microbiota and innate immunity receptor NOD2 in Crohn disease and colorectal cancer. [Doctoral Dissertation]. Université Lille II – Droit et Santé 2012. Available from: http://www.theses.fr/2012LIL2S008
Leiden University
19.
Willems, M.M.J.H.P.
Design and synthesis of NLR and TLR based ligand-antigen conjugates.
Degree: 2012, Leiden University
URL: http://hdl.handle.net/1887/20082
► The mammalian immune system protects, amongst others, against invading pathogens and consists of an innate and adaptive component. The innate system is the first line…
(more)
▼ The mammalian immune system protects, amongst others, against invading pathogens and consists of an innate and adaptive component. The innate system is the first line of defense in which pattern recognition receptors, like TLR2, NOD1 and
NOD2 receptors, detect pathogen associated molecular patterns (PAMPS) that are specific for pathogens. PAMPs exhibit a broad structural variety and the exact molecular structures of ligands that bind to the corresponding PRRs are mostly unknown. The research presented in this Thesis is directed to the design, synthesis and immunological evaluation of new NOD1,
NOD2 and TLR2 ligands as well as conjugates in which these ligands are covalently bound to an antigenic OVA-derived peptide. The designed NLR and TLR ligand-antigen conjugates contribute to the insight of the processes of the mammalian immune system at molecular level. Further elucidation of pattern recognition receptor acti vation and antigen presentation with these conjugates may eventually result in synthetic vaccine modalities.
Advisors/Committee Members: Marel, G.A. van der, Codée, J.D.C., Filippov, D.V., Leiden University.
Subjects/Keywords: Peptide; Conjugate; Ligand; TLR2; NOD2; NOD1
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APA (6th Edition):
Willems, M. M. J. H. P. (2012). Design and synthesis of NLR and TLR based ligand-antigen conjugates. (Doctoral Dissertation). Leiden University. Retrieved from http://hdl.handle.net/1887/20082
Chicago Manual of Style (16th Edition):
Willems, M M J H P. “Design and synthesis of NLR and TLR based ligand-antigen conjugates.” 2012. Doctoral Dissertation, Leiden University. Accessed March 09, 2021.
http://hdl.handle.net/1887/20082.
MLA Handbook (7th Edition):
Willems, M M J H P. “Design and synthesis of NLR and TLR based ligand-antigen conjugates.” 2012. Web. 09 Mar 2021.
Vancouver:
Willems MMJHP. Design and synthesis of NLR and TLR based ligand-antigen conjugates. [Internet] [Doctoral dissertation]. Leiden University; 2012. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/1887/20082.
Council of Science Editors:
Willems MMJHP. Design and synthesis of NLR and TLR based ligand-antigen conjugates. [Doctoral Dissertation]. Leiden University; 2012. Available from: http://hdl.handle.net/1887/20082
Texas A&M University
20.
Taylor, Kristen Hawkins.
Genetic analyses of bovine CARD15, a putative disease resistance gene.
Degree: PhD, Genetics, 2004, Texas A&M University
URL: http://hdl.handle.net/1969.1/219
► Through a binding partner the CARD15 gene activates NF-kB, a molecule with a role in the initiation of the inflammatory immune response. The gene is…
(more)
▼ Through a binding partner the CARD15 gene activates NF-kB, a molecule with a role in the initiation of the inflammatory immune response. The gene is highly conserved in both structure and function in human and mouse and has recently been implicated as a disease resistance gene in Crohn's disease and Blau Syndrome in human. The gene's relationship to disease and its conservation between species suggests that it may also have a conserved role in bovine disease resistance. To elucidate the potential role of bovine CARD15 in disease resistance, the gene was characterized in cattle. Bovine CARD15 is located 4.2 cR5000 telomeric to ADCY7 on chromosome 18. It spans ~30 kb and is comprised of 12 exons, 11 of which are coding. Bovine CARD15 is expressed in many tissues, but is most abundant in peripheral blood leukocytes. An extensive comparative analysis between the bovine, mouse and human CARD15 genes revealed high levels of inter-species conservation in sequence, genomic structure and protein domains. Conserved putative regulatory motifs were identified in the three species comparison of the 5'UTR, 3'UTR and the intronic sequences flanking exons. Additionally, diverse regulatory motifs were identified in each of the species indicating an evolutionary divergence in the mechanisms of regulation of gene expression. To assess the extent of genetic diversity within bovine CARD15, 41 individuals from nine breeds representing two subspecies were sequenced and screened for polymorphisms. Thirty-six single nucleotide polymorphisms (SNPs) were identified including 26 within the gene transcript. Haplotypes were estimated for each individual and parsimonious SNP sets were identified with which the multi-locus Bos taurus and Bos indicus haplotypes may be reconstructed. There was a significantly higher rate of substitutions within Bos indicus than in Bos taurus. A significantly higher rate of nonsynonymous to synonymous substitutions was found in Bos taurus indicating that positive Darwinian selection is acting on the gene within this subspecies. Association analyses were performed between these SNP loci and haplotypes with Johne's disease. No overwhelming evidence for a simple causal relationship was detected. Assays are provided to screen populations of cattle for variation in the CARD15 gene.
Advisors/Committee Members: Womack, James E. (advisor), Derr, James N. (committee member), Adams, L. Garry (committee member), Roussel, Allen J. (committee member).
Subjects/Keywords: CARD15; NOD2; bovine; disease resistance; Crohn's; Johne's
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Taylor, K. H. (2004). Genetic analyses of bovine CARD15, a putative disease resistance gene. (Doctoral Dissertation). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/219
Chicago Manual of Style (16th Edition):
Taylor, Kristen Hawkins. “Genetic analyses of bovine CARD15, a putative disease resistance gene.” 2004. Doctoral Dissertation, Texas A&M University. Accessed March 09, 2021.
http://hdl.handle.net/1969.1/219.
MLA Handbook (7th Edition):
Taylor, Kristen Hawkins. “Genetic analyses of bovine CARD15, a putative disease resistance gene.” 2004. Web. 09 Mar 2021.
Vancouver:
Taylor KH. Genetic analyses of bovine CARD15, a putative disease resistance gene. [Internet] [Doctoral dissertation]. Texas A&M University; 2004. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/1969.1/219.
Council of Science Editors:
Taylor KH. Genetic analyses of bovine CARD15, a putative disease resistance gene. [Doctoral Dissertation]. Texas A&M University; 2004. Available from: http://hdl.handle.net/1969.1/219
21.
Bowcutt, Rowann.
Dendritic Cells as a Biomarker for Gut
Pathology.
Degree: 2012, University of Manchester
URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:166358
► Trichuris trichiura (T. Trichiura) is a large-intestinal dwelling nematode that affects over 1 billion people world-wide and thus has large global significance. Much of our…
(more)
▼ Trichuris trichiura (T. Trichiura) is a
large-intestinal dwelling nematode that affects over 1 billion
people world-wide and thus has large global significance. Much of
our understanding of T. trichiura infection comes from the study of
the mouse model Trichuris muris (T. muris). However, how the immune
system is initiated in response to helminth threat and how
inflammation and pathology are resolved in T. muris infection still
remain to be addressed. Here, I have attempted to provide insight
into these questions.Previous work has shown resistance to T. muris
infection is associated with the rapid recruitment of dendritic
cells (DCs) to the colonic epithelium via epithelial production of
CCL5 and CCL20. However, the epithelial-parasite interaction that
drives chemokine production is not known. Pattern recognition
receptor (PRRS) are critical mediators of pathogen recognition but
there is no known (PRR) specific for T. muris. Here, we address the
role of the cytosolic pattern recognition receptor
Nod2, the
location of which within the crypts correlates with the T. muris
niche. In WT mice, in response to infection, there was a rapid
influx of CD103+CD11c+ DCs into the colonic epithelium, whereas,
this recruitment was impaired in
Nod2 /- animals. In vitro and in
vivo experiments confirmed the impairment in DC recruitment in
Nod2-/- mice was attributable to the epithelial compartment.
Subsequent work revealed decreased production of epithelial
chemokines in the absence of functional
Nod2. Thus, we have shown a
novel role for
Nod2 in the initiation the immune response to T.
muris. We next addressed how pathology is regulated during T. muris
infection. Firstly we investigated the role of arginase and
Arg1-expressing macrophages in regulating pathology. My data showed
that, unlike other gastrointestinal helminths, arginase and
Arg1-expressing macrophages are not essential for resistance to T.
muris or effective resolution of helminth-induced inflammation. I
also addressed the role of DCs in the resolution of infection. DCs
can regulate immune responses via the anti-inflammatory cytokine
IL-10 and induction of regulatory T cells (Treg). I used an IL
10flox/floxCD11cCre transgenic model in which mice have DCs that
cannot make IL-10. I found no role for CD11c+ cell mediated IL-10
production in the regulation of pathogen induced pathology in
chronic T. muris infection. In summary I have been able to identify
factors in the initiation of immunity to T. muris namely epithelial
expression of
Nod2. However, as arginase, Arg1-expressing
macrophages and DC derived IL-10 appeared to play a redundant role
in T. muris infection, the question as to how infection induced
inflammation is resolved remains elusive.
Advisors/Committee Members: GRENCIS, RICHARD RK, Grencis, Richard, Cruickshank, Sheena.
Subjects/Keywords: Dendritic Cell; Nod2; Macrophage; Arginase; Trichuris muris
…34
Figure 3:
Structure of Nod2… …47
Figure 4:
Nod2 Signalling Pathway… …50
Chapter 2: A role for the pattern recognition receptor Nod2 in promoting recruitment of… …of CD103+ DCs to the colonic epithelium in Nod2-/- mice in
response to T.muris… …83
Figure 2:
Delayed recruitment of CD103+ DCs to the colonic epithelium in Nod2-/- mice…
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Bowcutt, R. (2012). Dendritic Cells as a Biomarker for Gut
Pathology. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:166358
Chicago Manual of Style (16th Edition):
Bowcutt, Rowann. “Dendritic Cells as a Biomarker for Gut
Pathology.” 2012. Doctoral Dissertation, University of Manchester. Accessed March 09, 2021.
http://www.manchester.ac.uk/escholar/uk-ac-man-scw:166358.
MLA Handbook (7th Edition):
Bowcutt, Rowann. “Dendritic Cells as a Biomarker for Gut
Pathology.” 2012. Web. 09 Mar 2021.
Vancouver:
Bowcutt R. Dendritic Cells as a Biomarker for Gut
Pathology. [Internet] [Doctoral dissertation]. University of Manchester; 2012. [cited 2021 Mar 09].
Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:166358.
Council of Science Editors:
Bowcutt R. Dendritic Cells as a Biomarker for Gut
Pathology. [Doctoral Dissertation]. University of Manchester; 2012. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:166358
22.
Feerick, Claire L.
Epigenetic regulation of NOD-like receptor activity and expression.
Degree: 2019, NUI Galway
URL: http://hdl.handle.net/10379/14971
► NOD-like receptors (NLRs) are a family of intracellular pathogen recognition receptors involved in the innate immune response. NOD1 and NOD2 are the best characterised members…
(more)
▼ NOD-like receptors (NLRs) are a family of intracellular pathogen recognition receptors involved in the innate immune response. NOD1 and NOD2 are the best characterised members of this family, and so are the focus of this research. These receptors have been linked to a wide range of chronic inflammatory diseases, including inflammatory bowel disease. Aberrant NOD1/NOD2 expression has been associated with these states of chronic inflammation. However, the mechanism underlying NOD1/NOD2 gene expression regulation has yet to be elucidated. Therefore, this thesis aimed to investigate whether epigenetic modifications play a significant role in regulating NOD1/NOD2 activity and expression. Epigenetic modifications are heritable patterns that surround the DNA and histones, altering expression of the underlying genes. DNA methylation and histone acetylation are the best characterised of these modifications and so their effects on NOD1/NOD2 were investigated in this thesis. The cell line models used to carry out this experimentation included; HCT116 intestinal epithelial cells and THP-1 monocytic cells. Pharmacological attempts were made to induce a hypomethylated, hyperacetylated or differentiated status, after which NOD1/NOD2 pro-inflammatory responses were quantified. Cells primed with a demethylating agent (5-Aza, 5-Aza-dC or DNMT3b-/-), or containing a DNMT3b genetic knockout (DNMT3b-/-) were found to be consistently more responsive to NOD1/NOD2 stimulation and had increased expression. Treatment with a histone deacetylase inhibitor (SAHA) or monocyte-to-macrophage differentiation (using PMA) exhibited less conclusive effects on NOD1/NOD2 activity and expression. In conclusion, the novel experimentation carried out in this thesis suggests for the first time that NOD1/NOD2 receptor activity and expression are possibly regulated directly by DNA methylation. Future experimentation, involving DNA methylation pattern analysis, could be carried out to confirm this finding.
2023-02-18
Advisors/Committee Members: McKernan, Declan, Hardiman Research Scholarship, NUI Galway.
Subjects/Keywords: NOD-Like Receptors; Epigenetics; DNA methylation; Inflammation; Expression Regulation; Inflammatory Bowel Disease; NOD1; NOD2; Medicine; Pharmacology and Therapeutics
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Feerick, C. L. (2019). Epigenetic regulation of NOD-like receptor activity and expression. (Thesis). NUI Galway. Retrieved from http://hdl.handle.net/10379/14971
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Feerick, Claire L. “Epigenetic regulation of NOD-like receptor activity and expression.” 2019. Thesis, NUI Galway. Accessed March 09, 2021.
http://hdl.handle.net/10379/14971.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Feerick, Claire L. “Epigenetic regulation of NOD-like receptor activity and expression.” 2019. Web. 09 Mar 2021.
Vancouver:
Feerick CL. Epigenetic regulation of NOD-like receptor activity and expression. [Internet] [Thesis]. NUI Galway; 2019. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/10379/14971.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Feerick CL. Epigenetic regulation of NOD-like receptor activity and expression. [Thesis]. NUI Galway; 2019. Available from: http://hdl.handle.net/10379/14971
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cambridge
23.
Bhattacharyya, Joya.
Proteins involved in the pathogenesis of Crohn’s Disease.
Degree: PhD, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/301508
Subjects/Keywords: Crohn's; Proteins; Pathogenesis; ER Stress; FAMIN; Metabolic; NOD2
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APA ·
Chicago ·
MLA ·
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Export
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APA (6th Edition):
Bhattacharyya, J. (n.d.). Proteins involved in the pathogenesis of Crohn’s Disease. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/301508
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Chicago Manual of Style (16th Edition):
Bhattacharyya, Joya. “Proteins involved in the pathogenesis of Crohn’s Disease.” Doctoral Dissertation, University of Cambridge. Accessed March 09, 2021.
https://www.repository.cam.ac.uk/handle/1810/301508.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
MLA Handbook (7th Edition):
Bhattacharyya, Joya. “Proteins involved in the pathogenesis of Crohn’s Disease.” Web. 09 Mar 2021.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Vancouver:
Bhattacharyya J. Proteins involved in the pathogenesis of Crohn’s Disease. [Internet] [Doctoral dissertation]. University of Cambridge; [cited 2021 Mar 09].
Available from: https://www.repository.cam.ac.uk/handle/1810/301508.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Council of Science Editors:
Bhattacharyya J. Proteins involved in the pathogenesis of Crohn’s Disease. [Doctoral Dissertation]. University of Cambridge; Available from: https://www.repository.cam.ac.uk/handle/1810/301508
Note: this citation may be lacking information needed for this citation format:
No year of publication.
University of Michigan
24.
Burberry, Aaron Phillip.
Understanding Pattern Recognition Receptor Signaling and its Effect on Hematopoietic Stem Cells.
Degree: PhD, Molecular & Cellular Pathology, 2013, University of Michigan
URL: http://hdl.handle.net/2027.42/102495
► Pattern recognition receptors (PRRs) sense unique and conserved structures common to many types of microorganisms and activate pro-inflammatory signaling cascades that are important for mounting…
(more)
▼ Pattern recognition receptors (PRRs) sense unique and conserved structures common to many types of microorganisms and activate pro-inflammatory signaling cascades that are important for mounting effective immune responses, but aberrant regulation of PRR signaling can lead to autoimmunity. Polymorphisms in
NOD2, an intracellular PRR, are associated with increased risk of developing the inflammatory bowel disorder Crohn’s disease. To gain insight into how
NOD2 signaling is regulated, we performed a genome-wide siRNA screen in which
NOD2-induced NF-κB activation was assessed using a luciferase reporter system. Using this strategy, we identified and validated hundreds of novel regulators of the
NOD2 and NF-κB signaling pathway, some of which were previously implicated in Crohn’s disease susceptibility. By comparing our results with publicly available protein-protein interaction databases, we were able to visualize networks of genes, including the linear ubiquitin chain assembly complex, that are important for mediating
NOD2-dependent responses. Classically, PRRs are thought to function in differentiated cells to orchestrate inflammation, but recent evidence suggests that hematopoietic stem cells (HSCs), which maintain production of all blood cells throughout life, express PRRs and could be important for supporting immune responses during infection though the mechanisms underlying this function are unclear. We found that systemic infection of mice with the gram negative bacterium Escherichia coli resulted in moderate reduction of HSC activity in bone marrow and vastly expanded HSC activity in spleen, indicative of extramedullary hematopoiesis. Expansion of splenic HSCs was reduced in mice deficient for the PRR TLR4 or the adaptor protein RIPK2, which is required for NOD1 and
NOD2 signaling, implicating PRRs in the regulation of HSCs during infection. PRR signaling in radio-resistant cells was important for promoting progenitor expansion in spleen, suggesting an indirect mechanism. We found that expansion of splenic HSCs was dependent on dual activation of NOD1 and TLR4 and production of granulocyte-colony stimulating factor. Altogether, these results provide a global view of the mechanisms that regulate PRR signaling and provide insight into the pathways that facilitate extramedullary hematopoiesis in the context of infection.
Advisors/Committee Members: Nunez, Gabriel (committee member), Gumucio, Deborah L. (committee member), Lukacs, Nicholas W. (committee member), Ferguson, David O. (committee member).
Subjects/Keywords: Genome-wide SiRNA Screen to Identify Regulators of NOD2; Model of Bacterial Infection to Assess HSC Function and Localization; Implications for Crohn's Disease and Extramedullary Hematopoiesis; Pathology; Health Sciences; Science
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APA ·
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Manager
APA (6th Edition):
Burberry, A. P. (2013). Understanding Pattern Recognition Receptor Signaling and its Effect on Hematopoietic Stem Cells. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/102495
Chicago Manual of Style (16th Edition):
Burberry, Aaron Phillip. “Understanding Pattern Recognition Receptor Signaling and its Effect on Hematopoietic Stem Cells.” 2013. Doctoral Dissertation, University of Michigan. Accessed March 09, 2021.
http://hdl.handle.net/2027.42/102495.
MLA Handbook (7th Edition):
Burberry, Aaron Phillip. “Understanding Pattern Recognition Receptor Signaling and its Effect on Hematopoietic Stem Cells.” 2013. Web. 09 Mar 2021.
Vancouver:
Burberry AP. Understanding Pattern Recognition Receptor Signaling and its Effect on Hematopoietic Stem Cells. [Internet] [Doctoral dissertation]. University of Michigan; 2013. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/2027.42/102495.
Council of Science Editors:
Burberry AP. Understanding Pattern Recognition Receptor Signaling and its Effect on Hematopoietic Stem Cells. [Doctoral Dissertation]. University of Michigan; 2013. Available from: http://hdl.handle.net/2027.42/102495
25.
Choi, Aaron.
IL-32-Derived Dendritic Cells Cross-Present Defined Mycobacterium leprae Antigens to CD8+ T cells.
Degree: Microbiology, Immunology, & Molecular Genetics, 2018, UCLA
URL: http://www.escholarship.org/uc/item/8mg9460b
► Leprosy is a human disease caused by the intracellular pathogen Mycobacterium leprae. By investigating leprosy, we discovered a novel pathway involving NOD2-mediated induction of interleukin-32…
(more)
▼ Leprosy is a human disease caused by the intracellular pathogen Mycobacterium leprae. By investigating leprosy, we discovered a novel pathway involving NOD2-mediated induction of interleukin-32 (IL-32) triggering the differentiation of M. leprae infected monocytes into CD1+ dendritic cells (DCs) with professional antigen presenting cell function. These IL-32-derived DCs were able to “cross-present” antigen, that is capture exogenous antigen via the endocytic pathway and then present processed peptides via MHC class I to CD8+ T cells. It was also discovered that key components of the NOD2->IL-32->CD1+ DC pathway were highly expressed only in lesions of leprosy patients with cell-mediated immunity. We hypothesized that cross-presentation of M. leprae antigens by IL-32-derived DCs resulted in the activation of MHC class I-restricted CD8+ T cells. To test our hypothesis, we established CD8+ T cell clones from leprosy patients to putatively secreted M. leprae antigens. IL-32-derived DCs were able to cross-present exogenous recombinant M. leprae protein as well as live M. leprae to the CD8+ T cell clones. We conclude that IL-32-induced cross-presentation may play a role in CD8+ T cell responses in leprosy.
Subjects/Keywords: Immunology; antigen presentation; CD8; Cross-presentation; IL-32; Leprosy; NOD2
…formation of immune
complexes and fail to restrict M. leprae growth.
INTERLEUKIN-32
NOD2 is a… …activation of NOD2 in monocytes induced the production of IL-3213. In turn, NOD2
activation induced… …demonstrated by the high expression of NOD2, IL-32,
4
and CD1+ DCs in skin lesions of T-lep… …patients compared to that of L-lep patients (Figure 1.5).
Furthermore, NOD2… …components of the NOD2®IL-32®CD1+ DC pathway are highly
expressed in T-lep vs. L-lep lesions…
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APA ·
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APA (6th Edition):
Choi, A. (2018). IL-32-Derived Dendritic Cells Cross-Present Defined Mycobacterium leprae Antigens to CD8+ T cells. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/8mg9460b
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Choi, Aaron. “IL-32-Derived Dendritic Cells Cross-Present Defined Mycobacterium leprae Antigens to CD8+ T cells.” 2018. Thesis, UCLA. Accessed March 09, 2021.
http://www.escholarship.org/uc/item/8mg9460b.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Choi, Aaron. “IL-32-Derived Dendritic Cells Cross-Present Defined Mycobacterium leprae Antigens to CD8+ T cells.” 2018. Web. 09 Mar 2021.
Vancouver:
Choi A. IL-32-Derived Dendritic Cells Cross-Present Defined Mycobacterium leprae Antigens to CD8+ T cells. [Internet] [Thesis]. UCLA; 2018. [cited 2021 Mar 09].
Available from: http://www.escholarship.org/uc/item/8mg9460b.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Choi A. IL-32-Derived Dendritic Cells Cross-Present Defined Mycobacterium leprae Antigens to CD8+ T cells. [Thesis]. UCLA; 2018. Available from: http://www.escholarship.org/uc/item/8mg9460b
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Freie Universität Berlin
26.
Büning, Carsten.
Influence of genetic variants on development and course of inflammatory bowel
diseases.
Degree: 2010, Freie Universität Berlin
URL: https://refubium.fu-berlin.de/handle/fub188/13954
► Recent moleculargenetic studies have increased the number of putative genetic variants to be involved in the pathophysiology of inflammatory bowel diseases (IBD). This has highlighted…
(more)
▼ Recent moleculargenetic studies have increased the number of putative genetic
variants to be involved in the pathophysiology of inflammatory bowel diseases
(IBD). This has highlighted new and unexpected pathways, such aus autophagy
and IL23-signalling for IBD development. One unsolved phenomenen in IBD is a
disturbed epithelial barrier function that is suggested to increase e.g.
bacterial antigen uptake and thus support chronic inflammation. From a
clinicians point of view, genotyping for specific variants should help to
improve diagnosis, predict disease behaviour and foresee response to medical
treatment. This would help to identify patients with severe disease behaviour
and improve therapy. Although numerous variants have been found so far, we
could show in different populations that mutations in the
NOD2 gene are
assocaietd with an aggressive disease behaviour: early onset, ileocecal
resections early within the disease, and frequent surgical recurrence. Future
studies should therefore estimate whether aggressive treatment in patients
positive for
NOD2 mutations would benefit from a more aggressive therapy. Such
a significant genotype phenotype correlation was not observed for any other of
the variants analysed in our studies, such as p.Arg381Gln within IL23R and
p.Thr300Ala within ATG16L1. In addition, we have showen that a frameshift
mutation within
NOD2, p.Leu1007fs, is associated with an increased intestinal
permeability in Crohn’s disease. Furthermore, variants in the Myosin IXb gene
also increase the risk for an increased intestinal permeability. With respect
to many other variants in genes like IL23R, ATG16L1, DLG5, CD14, TLR4, CARD8,
no such association was observed. Despite these new and important findings, a
lot of work needs to be done to clearly define the phenotype relationship of
IBD genetics. Furthermore the molecular mechanism of how
NOD2 and Myosin IXb
variants contribute to barrier dysfunction need to be identified.
Advisors/Committee Members: [email protected] (contact), m (gender), Prof. Dr. med. Jürgen Schölmerich (firstReferee), Prof. Dr. med. Markus Lerch (furtherReferee).
Subjects/Keywords: Inflammatory bowel disease; Crohn's disease; ulcerative colitis; NOD2; ATG16L1; IL23R; permeability; phenotype; genetics; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit
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APA (6th Edition):
Büning, C. (2010). Influence of genetic variants on development and course of inflammatory bowel
diseases. (Thesis). Freie Universität Berlin. Retrieved from https://refubium.fu-berlin.de/handle/fub188/13954
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Büning, Carsten. “Influence of genetic variants on development and course of inflammatory bowel
diseases.” 2010. Thesis, Freie Universität Berlin. Accessed March 09, 2021.
https://refubium.fu-berlin.de/handle/fub188/13954.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Büning, Carsten. “Influence of genetic variants on development and course of inflammatory bowel
diseases.” 2010. Web. 09 Mar 2021.
Vancouver:
Büning C. Influence of genetic variants on development and course of inflammatory bowel
diseases. [Internet] [Thesis]. Freie Universität Berlin; 2010. [cited 2021 Mar 09].
Available from: https://refubium.fu-berlin.de/handle/fub188/13954.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Büning C. Influence of genetic variants on development and course of inflammatory bowel
diseases. [Thesis]. Freie Universität Berlin; 2010. Available from: https://refubium.fu-berlin.de/handle/fub188/13954
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
27.
Παχούλα, Ιωάννα.
Γενετική προδιάθεση σε παιδιά με ιδιοπαθή φλεγμονώδη νόσο του εντέρου.
Degree: 2011, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ)
URL: http://hdl.handle.net/10442/hedi/27892
► The present work aims to study genetic polymorphisms in Ulcerative Colitis (UC) and Crohn‘s Disease (CD) pediatric patients of Greek origin. To our knowledge this…
(more)
▼ The present work aims to study genetic polymorphisms in Ulcerative Colitis (UC) and Crohn‘s Disease (CD) pediatric patients of Greek origin. To our knowledge this is the first attempt to search for genetic markers possibly involved in inflammatory bowel disease (IBD) development in pediatric patients of Greek ethnicity.
Subjects studied and methods used:
125 Greek children with IBD (15 with UC and 110 with CD) aged 2.4 to 16.3 years at diagnosis as well as 659 healthy individuals of Greek origin used as controls were included in the study .
Diagnosis of IBD was based on clinical, radiological, endoscopic and histological examination.
Cytokines and cytokine receptors polymorphisms at the level of SNPs (IL1α-889, IL1β-511, IL1β+3962, IL1β-R pst 1 1970, IL1RA mspa1 11100, IL4-+1902, IL12-1188, TGFβ codon10, TGFβ codon25, TNFα-308, TNFα-238, IL2-330, IL2+166, IL4-1098, IL4-590, IL4-33,IL6-174, IL6 nt565, IL 10-1082, IL10-819 & IL10-592) were genotyped by PCR-SSP molecular technique (University of Heidelberg kit).
Genetic polymorphisms of NOD2/CARD15 (R702W, G908R and 3020insC), ATG 16L1 (rs2241880A/G) and IL23R (rs11209026 (R381Q)) were also determined but only in children (No 110) with CD. PCR or PCR-RFLP technique was used for NOD2/CARD15 gene polymorphism analysis. ATG16L1 and IL23R gene polymorphisms were genotyped by PCR and melting curve analysis, using a pair of fluorescence resonance energy transfer (FRET) probes.
Results
1. Statistically significant increase of IL-10 promoter phenotype-1082AG was found in patients with IBD (p=0.05), whereas a positive statically significant association (p=0.02) of IL-10 promoter phenotype -592CC was observed only in patients with CD. Regarding the IL-10 promoter haplotypes (1082G>A, -819T>C, -592A>C) only -1082AG phenotypes where found to predominate in IBD patients, in particular in UC patients.
2. The polymorphism 3020insC in NOD2/CARD15 was significantly higher in children with CD than in controls (p<0.0001). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease with or without colonic involvement.
3. Genotype GG of ATG16L1 rs2241880 polymorphism was significantly higher in children with CD than in controls (p=0.019).
4. Genotype RQ of IL23R rs11209026 polymorphism was under represented in pediatric CD patients (p=0.012).
5. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms, according to our findings, did not influence CD phenotype.
Conclusion:
Our results indicate that genetic polymorphisms involved in inflammatory immune response (ILs, NOD2/CARD15 and autophagy), contribute to IBD pathogenesis and could be used as genetic markers of IBD susceptibility.
Subjects/Keywords: Ιδιοπαθής φλεγμονώδης εντερική νόσος; Ελκώδης κολίτιδα; Νόσος Crohn; Γενετική προδιάθεση; Κυτταροκίνες; Πολυμορφισμοί; Inflammatory Bowel Diseases (IBD); Ulcerative colitis; Crohn's disease; Genetic predisposition; Cytokines; NOD2/CARDIS; ATG16L1; Polymorphisms
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APA ·
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CSE |
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APA (6th Edition):
Παχούλα, . . (2011). Γενετική προδιάθεση σε παιδιά με ιδιοπαθή φλεγμονώδη νόσο του εντέρου. (Thesis). National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Retrieved from http://hdl.handle.net/10442/hedi/27892
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Παχούλα, Ιωάννα. “Γενετική προδιάθεση σε παιδιά με ιδιοπαθή φλεγμονώδη νόσο του εντέρου.” 2011. Thesis, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Accessed March 09, 2021.
http://hdl.handle.net/10442/hedi/27892.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Παχούλα, Ιωάννα. “Γενετική προδιάθεση σε παιδιά με ιδιοπαθή φλεγμονώδη νόσο του εντέρου.” 2011. Web. 09 Mar 2021.
Vancouver:
Παχούλα . Γενετική προδιάθεση σε παιδιά με ιδιοπαθή φλεγμονώδη νόσο του εντέρου. [Internet] [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2011. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/10442/hedi/27892.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Παχούλα . Γενετική προδιάθεση σε παιδιά με ιδιοπαθή φλεγμονώδη νόσο του εντέρου. [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2011. Available from: http://hdl.handle.net/10442/hedi/27892
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
28.
Brooks, Michelle Nichole.
Nucleotide-binding Oligomerization Domain Containing 2
Characterization and Function during Mycobacterium tuberculosis
Infection of Human Macrophages.
Degree: PhD, Microbiology, 2011, The Ohio State University
URL: http://rave.ohiolink.edu/etdc/view?acc_num=osu1312480140
► Macrophages are important innate immune regulators in the recognition and clearance of invading pathogens. Mycobacterium tuberculosis (M.tb), which causes tuberculosis, is a host-adapted intracellular…
(more)
▼ Macrophages are important innate immune
regulators in the recognition and clearance of invading pathogens.
Mycobacterium tuberculosis (M.tb), which causes tuberculosis, is a
host-adapted intracellular pathogen of macrophages. Intracellular
pattern recognition receptors in macrophages such as
nucleotide-binding oligomerization domain (NOD) proteins regulate
pro-inflammatory cytokine production.
NOD2-mediated signaling
pathways in response to M.tb have been studied primarily in mouse
models and cell lines but not in primary human macrophages. Work in
this dissertation examined whether
NOD2 is expressed in human
macrophages, controls the growth of M.tb, and functions in
inducible nitric oxide synthase (iNOS) and novel protein kinase c
(PKC) signaling pathways. We examined
NOD2
expression during monocyte differentiation and observed a marked
increase in
NOD2 transcript and protein following 2-3 days in
culture. Pre-treatment of human monocyte-derived and alveolar
macrophages with the
NOD2 agonist muramyl dipeptide enhanced
production of TNF-α and IL-1β in response to M.tb and M. bovis BCG
(BCG) in a receptor interacting protein 2 (RIP2)-dependent fashion.
The
NOD2-mediated cytokine response was significantly reduced
following knockdown of
NOD2 expression by using small interfering
RNA (siRNA) in human macrophages. Finally,
NOD2 controlled the
growth of both M.tb and BCG in human macrophages, whereas
controlling only BCG growth in murine macrophages. Together, our
results provide evidence that
NOD2 is an important intracellular
receptor in regulating the host response to M.tb and BCG infection
in human macrophages. Our observation of
enhanced growth in
NOD2 deficient cells at 24 hours (h) is of
interest because during this time M.tb is becoming acclimated to
the macrophage. This led us to examine the involvement of
NOD2 in
early innate immune responses. In order to study new biological
functions and molecular mechanisms of
NOD2 during early M.tb
infection of human macrophages, we performed expression profiling
of M.tb-infected
NOD2 deficient macrophages using a microarray.
Notably, we identified that inducible nitric oxide synthase (iNOS)
expression is regulated by
NOD2 during M.tb infection. iNOS
expression is enhanced at 24 and 48 h after M.tb and BCG incubation
in human macrophages. Our data show iNOS expression is decreased in
NOD2 deficient cells stimulated with M.tb and the M.tb-specific
NOD2 agonist N-glycolylated muramyl dipeptide (GMDP), indicating
that
NOD2 is involved in iNOS protein expression. These data
provide evidence for a novel pathway involving
NOD2 that controls
M.tb growth in human macrophages through the regulation of iNOS
expression. We examined other potential signaling
partners for
NOD2 in human macrophages. Data show that the
NOD2
agonist, GMDP, stimulates phosphorylation and activation of PKCδ.
Corroborating these data,
NOD2 deficient cells stimulated with PMA
are significantly reduced in PKCδ phosphorylation. PMA is a known
stimulus for classical and novel PKC isoforms.…
Advisors/Committee Members: Schlesinger, Larry (Advisor).
Subjects/Keywords: Biology; Cellular Biology; Immunology; Innate immunity; Tuberculosis; Macrophage; NOD2
…Amer, M. Valdivia-Arenas, J. Park, G. Nuñez, and
L. Schlesinger. 2011. NOD2 controls the… …19
1.11 NOD2 signaling cascade… …19
1.12 NOD2 and TLR crosstalk… …22
1.13 NOD2 and microbial immunity… …23
1.14 NOD2 and inflammatory diseases…
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Brooks, M. N. (2011). Nucleotide-binding Oligomerization Domain Containing 2
Characterization and Function during Mycobacterium tuberculosis
Infection of Human Macrophages. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1312480140
Chicago Manual of Style (16th Edition):
Brooks, Michelle Nichole. “Nucleotide-binding Oligomerization Domain Containing 2
Characterization and Function during Mycobacterium tuberculosis
Infection of Human Macrophages.” 2011. Doctoral Dissertation, The Ohio State University. Accessed March 09, 2021.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1312480140.
MLA Handbook (7th Edition):
Brooks, Michelle Nichole. “Nucleotide-binding Oligomerization Domain Containing 2
Characterization and Function during Mycobacterium tuberculosis
Infection of Human Macrophages.” 2011. Web. 09 Mar 2021.
Vancouver:
Brooks MN. Nucleotide-binding Oligomerization Domain Containing 2
Characterization and Function during Mycobacterium tuberculosis
Infection of Human Macrophages. [Internet] [Doctoral dissertation]. The Ohio State University; 2011. [cited 2021 Mar 09].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1312480140.
Council of Science Editors:
Brooks MN. Nucleotide-binding Oligomerization Domain Containing 2
Characterization and Function during Mycobacterium tuberculosis
Infection of Human Macrophages. [Doctoral Dissertation]. The Ohio State University; 2011. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1312480140
29.
Κουνδουράκης, Αιμίλιος.
Διερεύνηση της γενετικής προδιάθεσης του ελληνικού πληθυσμού στη σαρκοείδωση.
Degree: 2009, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ)
URL: http://hdl.handle.net/10442/hedi/26689
► Sarcoidosis, similarly to Crohn’s disease, is a complex and multifactorial granulomatous disease of unknown etiology. They are both characterized by chronic inflammation and show similar…
(more)
▼ Sarcoidosis, similarly to Crohn’s disease, is a complex and multifactorial granulomatous disease of unknown etiology. They are both characterized by chronic inflammation and show similar clinical presentation and immunopathophysiology. Both sarcoidosis and Crohn’s disease are characterized by an immune response to a unknown target, with monocyte and T-cell activation and granuloma formation in affected organs. The belief that a genetic suscetibility to the development of sarcoidosis exists was derived from observations of familiar clustering of sarcoidosis cases and racial differences in disease prevalence.Taking into account the remarcable similarity in the immunopathophysiology of sarcoidosis and Crohn’s disease, and in further exploring the genetic backround of sarcoidosis in order to research the genetic suscetibility of the Greek population to develop the disease, we study gene polymorphisms of certain genes, known for their implication in Crohn’s disease, since they are involved in the recognition of bacterial lipopolysaccharides and in the subsequent activation of NFκ-B.These polymorphisms are in the CARD15/NOD2 gene (G908R, R702W and 3020insC), as well as mutations in the promoter of the CD14 gene (T/C at position -159) and in the Toll-like receptor-4 gene (TLR-4; Asp299Gly and Thr399Ile). We also explored a number of polymorphisms at the NRAMP1 gene, which has been associated with suscetibility to inflammatory or autoimmune disorders, icluding sarcoidosis, and mycobacterial infections, such as tubecolosis .Another goal of the present study was to correlate our results with the determination of the frequency of detection of Μycobacterium tubercolosis and Propionibacterium granulosum strains from the Greek sarcoid patients in order to evaluate the possible involvement of these agents in sarcoidosis.Our results suggests that the G908R polymorphism of the CARD15/NOD2 gene, the T allele and TT genotype of the CD14 gene and the allele 3 at the functional 5’(GT)n repeat polymorphism of the NRAMP1 gene are associated with sarcoidosis in the Greek population. Also our results concerning the detection of mycobacterial strains from the samples of the Greek sarcoid patients provide evidence that infectious agents might trigger sarcoidosis in genetically predisposed patients by the activation of the innate immune system response.
Η σαρκοείδωση όπως και η νόσος του Crohn αποτελούν φλεγμονώδεις νόσους αγνώστου αιτιολογίας, οι οποίες χαρακτηρίζονται από μια εκτεταμένη ανοσολογική απόκριση προς ένα αδιευκρίνιστο ακόμα στόχο, με ενεργοποίηση των μονοκυττάρων και των Τ-κυττάρων και από το σχηματισμό κοκκιωμάτων στα προσβεβλημένα όργανα. Λαμβάνοντας υπ’ όψιν την αξιοσημείωτη επικάλυψη στην ανοσοπαθοφυσιολογία των δύο ασθενειών,στην προσπάθειά μας να διερευνήσουμε την γενετική προδιάθεση του Ελληνικού πληθυσμού στην σαρκοείδωση καθίσταται σημαντική η μελέτη της εμπλοκής συγκεκριμένων γονιδιακών πολυμορφισμών που σχετίζονται με την προδιάθεση στη νόσο του Crohn προκαλώντας διαταραχές στην ενεργοποίηση του NFκ-Β σε απόκριση…
Subjects/Keywords: Σαρκοείδωση; Ολιτοτυποποίηση; Γονίδιο CARD 15 / NOD2; Γονίδιο CD 14; Γονίδιο TLR - 4; Γονίδιο NRAMP1; Sarcoidosis; Spoligotyping; CARD 15 / NOD2 gene; CD 14 gene; TLR - 4 gene; Gene NRAMP1
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APA ·
Chicago ·
MLA ·
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CSE |
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APA (6th Edition):
Κουνδουράκης, . . (2009). Διερεύνηση της γενετικής προδιάθεσης του ελληνικού πληθυσμού στη σαρκοείδωση. (Thesis). National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Retrieved from http://hdl.handle.net/10442/hedi/26689
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Κουνδουράκης, Αιμίλιος. “Διερεύνηση της γενετικής προδιάθεσης του ελληνικού πληθυσμού στη σαρκοείδωση.” 2009. Thesis, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Accessed March 09, 2021.
http://hdl.handle.net/10442/hedi/26689.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Κουνδουράκης, Αιμίλιος. “Διερεύνηση της γενετικής προδιάθεσης του ελληνικού πληθυσμού στη σαρκοείδωση.” 2009. Web. 09 Mar 2021.
Vancouver:
Κουνδουράκης . Διερεύνηση της γενετικής προδιάθεσης του ελληνικού πληθυσμού στη σαρκοείδωση. [Internet] [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2009. [cited 2021 Mar 09].
Available from: http://hdl.handle.net/10442/hedi/26689.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Κουνδουράκης . Διερεύνηση της γενετικής προδιάθεσης του ελληνικού πληθυσμού στη σαρκοείδωση. [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2009. Available from: http://hdl.handle.net/10442/hedi/26689
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
30.
Yang, Yibin.
The Role of Rip2 Protein in the Nod Mediated Innate Immune Response: A Dissertation.
Degree: Cancer Biology, Molecular, Cell and Cancer Biology, 2010, U of Massachusetts : Med
URL: https://escholarship.umassmed.edu/gsbs_diss/475
► The Rip2 kinase contains a caspase recruitment domain (CARD) and has been implicated in the activation of the transcriptional factor NF-кB downstream of Nod-like…
(more)
▼ The Rip2 kinase contains a caspase recruitment domain (CARD) and has been implicated in the activation of the transcriptional factor NF-кB downstream of Nod-like receptors. However, how Rip2 mediates innate immune responses is still largely unclear. We show that Rip2 and IKK-γ become stably polyubiquitinated upon treatment of cells with the
Nod2 ligand, muramyl dipeptide. We demonstrate a requirement for the E2 conjugating enzyme Ubc13, the E3 ubiquitin ligase Traf6 and the ubiquitin activated kinase Tak1 in
Nod2-mediated NF-кB activation. We also show that
M. tuberculosisinfection stimulates Rip2 polyubiquitination. Collectively, this study revealed that the
Nod2 pathway is ubiquitin regulated and that Rip2 employs a ubiquitin-dependent mechanism to achieve NF-кB activation.
We also demonstrate that intraphagosomal
M. tuberculosis stimulates the cytosolic
Nod2 pathway. We show that upon Mtb infection,
Nod2 recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depends entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the
Nod2/Rip2/Irf5 pathway. Thus, the
Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to Mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system.
Advisors/Committee Members: Michelle Kelliher, Ph.D..
Subjects/Keywords: Receptor-Interacting Protein Serine-Threonine Kinase 2; Nod2 Signaling Adaptor Protein; Ubiquitin; NF-kappa B; Mycobacterium tuberculosis; Amino Acids, Peptides, and Proteins; Bacteria; Enzymes and Coenzymes; Hemic and Immune Systems; Immunology and Infectious Disease
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Yang, Y. (2010). The Role of Rip2 Protein in the Nod Mediated Innate Immune Response: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/475
Chicago Manual of Style (16th Edition):
Yang, Yibin. “The Role of Rip2 Protein in the Nod Mediated Innate Immune Response: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 09, 2021.
https://escholarship.umassmed.edu/gsbs_diss/475.
MLA Handbook (7th Edition):
Yang, Yibin. “The Role of Rip2 Protein in the Nod Mediated Innate Immune Response: A Dissertation.” 2010. Web. 09 Mar 2021.
Vancouver:
Yang Y. The Role of Rip2 Protein in the Nod Mediated Innate Immune Response: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2021 Mar 09].
Available from: https://escholarship.umassmed.edu/gsbs_diss/475.
Council of Science Editors:
Yang Y. The Role of Rip2 Protein in the Nod Mediated Innate Immune Response: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/475
◁ [1] [2] ▶
. 
Open Access Theses and Dissertations
