subject:(jak vnit n )

1. Tardif, Nicolas. Mechanosignaling through Caveolae : A New Role for the Control of JAK-STAT Signaling : Mécano-signalisation par les cavéoles : un rôle nouveau dans le contrôle de la voie de signalisation JAK-STAT.

Degree: Docteur es, Aspects moléculaires et cellulaires de la biologie, 2018, Université Paris-Saclay (ComUE)

URL: http://www.theses.fr/2018SACLS337

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Les cavéoles sont des invaginations en forme de coupelle à la membrane plasmique. Ces organelles multifonctionnelles jouent entre autres, un rôle clé dans la mécano-protection… (more)

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Les cavéoles sont des invaginations en forme de coupelle à la membrane plasmique. Ces organelles multifonctionnelles jouent entre autres, un rôle clé dans la mécano-protection et la signalisation cellulaire. En effet, les cavéoles ont la faculté de s’aplanir en réponse à l’augmentation de la tension membranaire, afin de protéger la cellule des contraintes mécaniques. Les cavéoles jouant un rôle clé dans la signalisation cellulaire, nous avions émis l’hypothèse que le cycle mécano-dépendent de désassemblage/réassemblage des cavéoles constitue un interrupteur mécanique de certaines voies de signalisation. Ce projet consiste à élucider le mécanisme moléculaire responsable du contrôle de la voie de signalisation JAK-STAT par la mécanique des cavéoles. Dans ces travaux, nous avons pu démontré que la cavéoline-1 (Cav1), un constitutant essentiel des cavéoles est libérée et devient hautement mobile au niveau de la membrane plasmique. Considérant les propriétés de signalisation de Cav1, Nous avons testé l’effet du désassemblage des cavéoles sur la signalisation cellulaire. Un criblage à haut débit, nous a permis identifié la voie de signalisation JAK- STAT stimulée par l’IFN-α comme voie modèle pour cette étude. En effet, la transduction du signal JAK-STAT induit par l’IFN-α est modulée par la mécanique des cavéoles. Afin de disséquer le mécanisme moléculaire responsable du contrôle de la signalisation JAK-STAT par la mécanique des cavéoles, nous avons déterminé le rôle de Cav1 dans ce contrôle. Nous avons observé que Cav1 est un régulateur négatif de la phosphorylation de STAT3 dépendante de la kinase JAK1. De plus, nous avons démontré que Cav1 interagit avec JAK1 en fonction de la tension membranaire. Nous avons également démontré que cette interaction Cav1-JAK1 fait intervenir le « scaffolding domain » de Cav1 (CSD), et que celui-ci est responsable de l’abolition de l’activité kinase de JAK1. Par conséquent, l’interaction de Cav1 avec JAK1 empêche l’activation de STAT3 par la kinase JAK1. Ces résultats démontrent que les cavéoles sont des organelles de mécano-signalisation, qui, lors d’un stress mécanique, libèrent de la Cav1 non cavéolaire capable d’inactiver la kinase JAK1, empêchant ainsi, la transduction du signal JAK-STAT.

Caveolae are small cup-shaped plasma membrane invaginations. These multifunctional organelles play a key role in cell mechanoprotection and cell signaling. Indeed our laboratory reported that caveolae have the ability to flatten out upon membrane tension increase, protecting cells from mechanical strains. Since caveolae play a key role in cell signaling we hypothesized that the mechano-dependent cycle of caveolae disassembly/reassembly may constitute a mechanical switch for signaling pathways. In this project, we elucidated the molecular mechanism underlying the control of JAK-STAT signaling by caveolae mechanics. We showed that caveolin-1 (Cav1), an essential caveolar component is released and become highly mobile at the plasma membrane under mechanical stress. Considering that caveolae are…

Advisors/Committee Members: Lamaze, Christophe (thesis director).

Subjects/Keywords: Mécanosignalisation; Mécanotransduction; Cavéoles; JAK-STAT; Mechanosignalling; Mechanotransduction; Caveolae; JAK-STAT

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tardif, N. (2018). Mechanosignaling through Caveolae : A New Role for the Control of JAK-STAT Signaling : Mécano-signalisation par les cavéoles : un rôle nouveau dans le contrôle de la voie de signalisation JAK-STAT. (Doctoral Dissertation). Université Paris-Saclay (ComUE). Retrieved from http://www.theses.fr/2018SACLS337

Chicago Manual of Style (16^th Edition):

Tardif, Nicolas. “Mechanosignaling through Caveolae : A New Role for the Control of JAK-STAT Signaling : Mécano-signalisation par les cavéoles : un rôle nouveau dans le contrôle de la voie de signalisation JAK-STAT.” 2018. Doctoral Dissertation, Université Paris-Saclay (ComUE). Accessed January 18, 2021. http://www.theses.fr/2018SACLS337.

MLA Handbook (7^th Edition):

Tardif, Nicolas. “Mechanosignaling through Caveolae : A New Role for the Control of JAK-STAT Signaling : Mécano-signalisation par les cavéoles : un rôle nouveau dans le contrôle de la voie de signalisation JAK-STAT.” 2018. Web. 18 Jan 2021.

Vancouver:

Tardif N. Mechanosignaling through Caveolae : A New Role for the Control of JAK-STAT Signaling : Mécano-signalisation par les cavéoles : un rôle nouveau dans le contrôle de la voie de signalisation JAK-STAT. [Internet] [Doctoral dissertation]. Université Paris-Saclay (ComUE); 2018. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2018SACLS337.

Council of Science Editors:

Tardif N. Mechanosignaling through Caveolae : A New Role for the Control of JAK-STAT Signaling : Mécano-signalisation par les cavéoles : un rôle nouveau dans le contrôle de la voie de signalisation JAK-STAT. [Doctoral Dissertation]. Université Paris-Saclay (ComUE); 2018. Available from: http://www.theses.fr/2018SACLS337

2. de Carvalho Leandro, Danilo. Análise da imunidade de Aedes Aegypti (Diptera: Culicidae) ao vírus dengue em populações de campo com competência vetorial diferenciada .

Degree: 2011, Universidade Federal de Pernambuco

URL: http://repositorio.ufpe.br/handle/123456789/1020

► Um dos determinantes envolvidos no complexo ciclo de transmissão da dengue é o nível de susceptibilidade do Aedes aegypti ao vírus dengue (DENV), ou seja,… (more)

Subjects/Keywords: Interação mosquito-DENV; Toll; JAK-STAT; RNAi.

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

de Carvalho Leandro, D. (2011). Análise da imunidade de Aedes Aegypti (Diptera: Culicidae) ao vírus dengue em populações de campo com competência vetorial diferenciada . (Thesis). Universidade Federal de Pernambuco. Retrieved from http://repositorio.ufpe.br/handle/123456789/1020

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

de Carvalho Leandro, Danilo. “Análise da imunidade de Aedes Aegypti (Diptera: Culicidae) ao vírus dengue em populações de campo com competência vetorial diferenciada .” 2011. Thesis, Universidade Federal de Pernambuco. Accessed January 18, 2021. http://repositorio.ufpe.br/handle/123456789/1020.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

de Carvalho Leandro, Danilo. “Análise da imunidade de Aedes Aegypti (Diptera: Culicidae) ao vírus dengue em populações de campo com competência vetorial diferenciada .” 2011. Web. 18 Jan 2021.

Vancouver:

de Carvalho Leandro D. Análise da imunidade de Aedes Aegypti (Diptera: Culicidae) ao vírus dengue em populações de campo com competência vetorial diferenciada . [Internet] [Thesis]. Universidade Federal de Pernambuco; 2011. [cited 2021 Jan 18]. Available from: http://repositorio.ufpe.br/handle/123456789/1020.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

de Carvalho Leandro D. Análise da imunidade de Aedes Aegypti (Diptera: Culicidae) ao vírus dengue em populações de campo com competência vetorial diferenciada . [Thesis]. Universidade Federal de Pernambuco; 2011. Available from: http://repositorio.ufpe.br/handle/123456789/1020

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

3. Amborn, Anna. JAK Medlemsbank och räntan : Ett räntefritt alternativ.

Degree: Business and Economic Studies, 2012, University of Gävle

URL: http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-12320

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Titel: JAK Medlemsbank och räntan – Ett räntefritt alternativ. Nivå: Kandidatnivå. Författare: Anna Amborn och Linda Elgestad. Handledare: Maria Fregidou-Malama. Datum: 2012-06-28. Syfte: Studien… (more)

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Titel: JAK Medlemsbank och räntan – Ett räntefritt alternativ. Nivå: Kandidatnivå. Författare: Anna Amborn och Linda Elgestad. Handledare: Maria Fregidou-Malama. Datum: 2012-06-28. Syfte: Studien syftar till att undersöka och analysera JAK Medlemsbanks syn på det ekonomiska systemet i allmänhet och räntan i synnerhet, samt undersöka om det går att låna pengar utan ränta. Vi belyser också att det finns dolda räntekostnader i det vi konsumerar.Metod: Metoden som använts är en kvalitativ metod och data har främst samlats in genom tre ostrukturerade intervjuer med anställda och engagerade personer inom JAK Medlemsbank. Material till teoriavsnittet har samlats in från databaser, artiklar och böcker. Resultat & slutsats: Studien visar att JAK Medlemsbank är vad den utger sig för att vara, alltså en räntefri bank. Dock är detta beroende av att ränta definieras som en arbetsfri inkomst dvs. en inkomst som inte täcker några verkliga kostnader. Studien visar att ett lån i JAK Medlemsbank ger en relativt hög månadskostnad vilket också gör att det krävs en hög månadsinkomst för att låna ett större belopp. Förslag till fortsattforskning: Det räntefria alternativet är ett relativt outforskat område vilket ger stora möjligheter till fortsatt forskning. Ett av dessa outforskade områden är räntans andel av priset på en vara. För att utforska detta område anser vi att det krävs mer tid då många företag verkat motvilliga att lämna ut sådan information. Uppsatsens bidrag: Studien har bidragit till att samla in information om JAK Medlemsbank, deras ideologi och verksamhet. Den bidrar också till att redogöra för att det finns ett räntefritt alternativ till de konventionella bankerna samt beskriver hur detta alternativ fungerar. Studien ger således en övergripande bild av JAK’s verksamhet samt belyser de nackdelar som räntan medför. Nyckelord: Räntefri, JAK Medlemsbank, ränta, avgift, lånekostnad, kooperativ.

Title: JAK Members bank and the interest rate – An interest-free alternative. Level: Final assignment for Bachelor Degree in Business Administration. Author: Anna Amborn och Linda Elgestad. Supervisor: Maria Fregidou-Malama. Date: 2012-06-06. Aim: The study aims to investigate and analyze the JAK Members bank view of the economic system in general and the interest rate in particular, and examine if it is possible to borrow money without interest. We also highlight that there is a hidden interest rate in what we consume. Method: The method used is a qualitative method and the data was mainly gathered through three unstructured interviews with employees and involved people in the JAK Members bank. Materials for the theory section were collected…

Subjects/Keywords: Räntefri; JAK Medlemsbank; ränta; avgift; lånekostnad; kooperativ

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Amborn, A. (2012). JAK Medlemsbank och räntan : Ett räntefritt alternativ. (Thesis). University of Gävle. Retrieved from http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-12320

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Amborn, Anna. “JAK Medlemsbank och räntan : Ett räntefritt alternativ.” 2012. Thesis, University of Gävle. Accessed January 18, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-12320.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Amborn, Anna. “JAK Medlemsbank och räntan : Ett räntefritt alternativ.” 2012. Web. 18 Jan 2021.

Vancouver:

Amborn A. JAK Medlemsbank och räntan : Ett räntefritt alternativ. [Internet] [Thesis]. University of Gävle; 2012. [cited 2021 Jan 18]. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-12320.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Amborn A. JAK Medlemsbank och räntan : Ett räntefritt alternativ. [Thesis]. University of Gävle; 2012. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-12320

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Notre Dame

4. Francis James Raycroft. Characterization of the JAK1 / Stat3 pathway during zebrafish retinal development and light-induced photoreceptor regeneration</h1>.

Degree: Biological Sciences, 2014, University of Notre Dame

URL: https://curate.nd.edu/show/jw827942h2c

► The zebrafish is an excellent model organism to use in the study of molecular pathways important in both retinal development and neuronal regeneration. The… (more)

▼ The zebrafish is an excellent model organism to use in the study of molecular pathways important in both retinal development and neuronal regeneration. The zebrafish shares similarities in eye development and morphology with all vertebrate eyes. However, unlike the mammalian retina, the zebrafish completely regenerates retinal neurons following injury . The source of regeneration are M?ller glial cells that dedifferentiate into a more primordial stem cell-like state, divide, and yield transiently amplifying progenitor cells that migrate to the site of damage and replenish the lost neuronal cell types. Dedifferentiating M?ller glia in the adult zebrafish retina experience reprogramming in DNA methylation and expression of transcription factors that are involved during normal retinal development (Pollak et al., 2013; Powell et al., 2013). Therefore, studying the cellular and molecular pathways important during retinal development may provide insight into the roles these genes play during regeneration in the adult retina. In an effort to identify pathways involved in early retinal development in zebrafish, a gene microarray analysis was performed, which demonstrated a significant up regulation in components of the JAK/Stat3 pathway, including Socs3a and Socs1. Immunoblots, immunohistochemistry, and in situ hybridization data confirmed that Stat3, Socs3a, and Socs1 were up regulated in the zebrafish eye between 3-5 days post-fertilization, time points associated with significant maturation of vision. Stat3, Socs3a, and Socs1 are initially expressed ubiquitously throughout the developing retina before showing a distinct localization within M?ller glial cells. Morpholino-mediated knockdown of Stat3, Socs3a, or Socs1 demonstrated that a loss of JAK/Stat3 function caused abnormal retinal cell death during development. A loss of either Socs1 or Socs3a resulted in decreased rhodopsin expression near the retinal margins of the developing zebrafish, while and a loss of Stat3 affected cone photoreceptor cell and M?ller glial cell maintenance. These results indicated that JAK/Stat3 signaling is important to the development of photoreceptor and M?ller glial cells as well as the maintenance of a healthy retina. The adult zebrafish retina regenerates following light-induced photoreceptor cell death. M?ller glial cells in light-damaged retinas divide yielding undifferentiated progenitors that migrate and differentiate to replace the lost rod and cone photoreceptors. We demonstrated previously that, following light-induced photoreceptor cell death, a loss of either TNFα or Stat3 reduced M?ller glial cell proliferation significantly, suggesting that the number of M?ller glia that reenter the cell cycle following retinal damage was dependent upon coordinated expression of TNFα and Stat3 (Nelson et al., 2013). Although it seems likely that TNFα initiates Stat3 signaling through a cytokine-receptor mediated pathway, a receptor linking the two proteins together has yet to be identified. Also, previous studies demonstrated that… Advisors/Committee Members: Dr. Robert A. Schulz, Committee Member, Dr. Paul W. Huber, Committee Member, Dr. David R. Hyde, Committee Chair, Dr. Joseph OTousa, Committee Member.

Subjects/Keywords: jak; stat3; socs; retina; zebrafish; regeneration

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APA (6^th Edition):

Raycroft, F. J. (2014). Characterization of the JAK1 / Stat3 pathway during zebrafish retinal development and light-induced photoreceptor regeneration</h1>. (Thesis). University of Notre Dame. Retrieved from https://curate.nd.edu/show/jw827942h2c

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Raycroft, Francis James. “Characterization of the JAK1 / Stat3 pathway during zebrafish retinal development and light-induced photoreceptor regeneration</h1>.” 2014. Thesis, University of Notre Dame. Accessed January 18, 2021. https://curate.nd.edu/show/jw827942h2c.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Raycroft, Francis James. “Characterization of the JAK1 / Stat3 pathway during zebrafish retinal development and light-induced photoreceptor regeneration</h1>.” 2014. Web. 18 Jan 2021.

Vancouver:

Raycroft FJ. Characterization of the JAK1 / Stat3 pathway during zebrafish retinal development and light-induced photoreceptor regeneration</h1>. [Internet] [Thesis]. University of Notre Dame; 2014. [cited 2021 Jan 18]. Available from: https://curate.nd.edu/show/jw827942h2c.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Raycroft FJ. Characterization of the JAK1 / Stat3 pathway during zebrafish retinal development and light-induced photoreceptor regeneration</h1>. [Thesis]. University of Notre Dame; 2014. Available from: https://curate.nd.edu/show/jw827942h2c

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Arizona

5. Younis, Usir. Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant Systems .

Degree: 2018, University of Arizona

URL: http://hdl.handle.net/10150/626756

► Asthma is a significant lung disease involving chronic inflammation and remodeling of the airways, resulting in reduced quality of life for those who suffer from… (more)

▼ Asthma is a significant lung disease involving chronic inflammation and remodeling of the airways, resulting in reduced quality of life for those who suffer from the condition. Current therapeutic guidelines suggest the use of inhaled corticosteroids for long-term anti-inflammatory relief to manage moderate to severe chronic asthma; however, inhaled corticosteroids fail to provide prophylactic or reversal treatment of damaged airways incurred by chronic asthma as well as exhibiting adverse side effects (skeletal complications, diabetes, and weight gain).Therefore, there is a need for a new type of drug therapy to address these gaps in the treatment of chronic asthma. There is growing interest aimed towards the inhibition of the Janus Kinase and Signal Transducer and Activator of Transcription (JAK-STAT) pathway for the treatment of asthma. Despite the promising opportunity to investigate this new pathway towards this clinical application, no published work is available using an established and characterized JAK 1/3 inhibitor for the treatment of chronic asthma delivered via inhalation. This work investigated tofacitinib citrate, a selective JAK 3 inhibitor, and its potential to be delivered locally to the lungs for the treatment of chronic asthma. Several preformulation studies were conducted to determine the basic physical and chemical properties of the compound and its free base, tofacitinib, for proper inhalational formulation development. The drug was delivered to BALB/c mice challenged with house dust mite (HDM) allergen via nebulization utilizing a nose-only chamber. After a three week dosing schedule, mice treated with tofacitinib citrate exhibited an increase in monocyte cell numbers with a simultaneous decrease in eosinophil cell count, gathered from BAL fluid. Further, the experimental groups treated with tofacitinib citrate had a decrease in total protein concentrations in comparison to the experimental groups that were only challenged with HDM or were both exposed to HDM and vehicle. These findings demonstrated that the proper formulation was developed for nebulized delivery of tofacitinib citrate, and that the compound was capable of reducing total protein concentrations and eosinophil cell recruitment, both recognized as biomarkers for an asthmatic response. Although significant work is still needed to be done, these data hold promise for the potential of a locally delivered JAK 3 inhibitor as a treatment for chronic asthma. Further, the solubility of tofacitinib citrate and five other pharmaceutical salts were determined in HFA 134a, HFA 227, and DFP with varying cosolvent content (0-20% v/v ethanol). The experimental solubilities of the free acid and base compounds were larger than the solubilities of their respective salts in all three systems for tofacitinib, albuterol, and salicylic acid. Warfarin, phenytoin, and ciprofloxacin had similar solubilities with their respective salt forms. Solubilities also increased with increasing cosolvent concentration for all compounds investigated. The model… Advisors/Committee Members: Myrdal, Paul B (advisor), Myrdal, Paul B. (committeemember), Gukasyan, Hovik (committeemember), Mayersohn, Michael (committeemember), Yalkowsky, Samuel (committeemember), Vaillancourt, Richard (committeemember).

Subjects/Keywords: asthma; HFA; inhalation; JAK-STAT; pMDI; tofacitinib

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Younis, U. (2018). Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant Systems . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/626756

Chicago Manual of Style (16^th Edition):

Younis, Usir. “Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant Systems .” 2018. Doctoral Dissertation, University of Arizona. Accessed January 18, 2021. http://hdl.handle.net/10150/626756.

MLA Handbook (7^th Edition):

Younis, Usir. “Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant Systems .” 2018. Web. 18 Jan 2021.

Vancouver:

Younis U. Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant Systems . [Internet] [Doctoral dissertation]. University of Arizona; 2018. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10150/626756.

Council of Science Editors:

Younis U. Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant Systems . [Doctoral Dissertation]. University of Arizona; 2018. Available from: http://hdl.handle.net/10150/626756

6. SILVA, Juan Luiz Coelho da. Impacto clínico e laboratorial de mutações no gene ASXL1 em pacientes com neoplasias mieloproliferativas .

Degree: 2016, Universidade Federal de Pernambuco

URL: http://repositorio.ufpe.br/handle/123456789/19535

► Algumas evidências destacam mutações no gene ASXL1 como um evento importante na evolução clínica de pacientes com neoplasias hematológicas, particularmente em leucemias mieloides agudas e… (more)

▼ Algumas evidências destacam mutações no gene ASXL1 como um evento importante na evolução clínica de pacientes com neoplasias hematológicas, particularmente em leucemias mieloides agudas e síndrome mielodisplásicas. Contudo, seu impacto prognóstico em neoplasias mieloproliferativas (NMP) ainda é pouco explorado. Aqui, nós caracterizamos 208 pacientes com NMP cromossomo Filadélfia (Ph) negativo (policitemia vera, PV; trombocitemia essencial, TE; mielofibrose primária, MFP), de acordo com mutações no gene ASXL1, e correlacionamos esses achados com características clinico-laboratoriais desses pacientes. A pesquisa das mutações foi realizada por sequenciamento sanger, em que polimorfismos germinativos e mutações sinonímias foram excluídas das análises. Mutações no ASXL1 foram detectadas em 22/208 pacientes (10%), das quais quatro foram observadas em pacientes com PV (4/54; 7%), onze em pacientes com TE (11/123; 9%) e sete com MFP (7/31; 22%). As características clínicas e laboratoriais foram similares entre pacientes com ASXL1 mutado e não mutado. Quando as entidades foram avaliadas individualmente (PV, TE e MFP), observou-se associação entre mutações no ASXL1 e idade mais avançada em pacientes com TE (P = 0,049) e desenvolvimento de esplenomegalia em pacientes com MFP (P = 0,026). Com uma mediana de seguimento de 5,1 anos (IC95%: 4,5 a 7,3 anos), 136 pacientes (65%) desenvolveram algum tipo de manifestação clínica, sendo o desenvolvimento de complicações vasculares o mais frequente (n=54; 26%), seguido por esplenomegalia (n=47; 22%), eventos hemorrágicos (n=30; 14%) e trombose (n=21; 10%). Mutações no gene ASXL1 não foram associadas com o desenvolvimento das referidas manifestações. Dentro deste seguimento, apenas dois pacientes evoluíram para síndrome mielodisplásica e um para leucemia mieloide aguda, todos sem mutações no gene ASXL1. Advisors/Committee Members: ARAUJO, Antonio Roberto Lucena de (advisor), BEZERRA, Marcos André Cavalcanti (advisor), http://lattes.cnpq.br/9519574368895128 (advisor).

Subjects/Keywords: Neoplasias mieloides; Modificadores epigenéticos; JAK-STAT; Prognóstico; Myeloid neoplasm; Epigenetic modifiers; JAK-STAT; Prognostic

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

SILVA, J. L. C. d. (2016). Impacto clínico e laboratorial de mutações no gene ASXL1 em pacientes com neoplasias mieloproliferativas . (Thesis). Universidade Federal de Pernambuco. Retrieved from http://repositorio.ufpe.br/handle/123456789/19535

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

SILVA, Juan Luiz Coelho da. “Impacto clínico e laboratorial de mutações no gene ASXL1 em pacientes com neoplasias mieloproliferativas .” 2016. Thesis, Universidade Federal de Pernambuco. Accessed January 18, 2021. http://repositorio.ufpe.br/handle/123456789/19535.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

SILVA, Juan Luiz Coelho da. “Impacto clínico e laboratorial de mutações no gene ASXL1 em pacientes com neoplasias mieloproliferativas .” 2016. Web. 18 Jan 2021.

Vancouver:

SILVA JLCd. Impacto clínico e laboratorial de mutações no gene ASXL1 em pacientes com neoplasias mieloproliferativas . [Internet] [Thesis]. Universidade Federal de Pernambuco; 2016. [cited 2021 Jan 18]. Available from: http://repositorio.ufpe.br/handle/123456789/19535.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

SILVA JLCd. Impacto clínico e laboratorial de mutações no gene ASXL1 em pacientes com neoplasias mieloproliferativas . [Thesis]. Universidade Federal de Pernambuco; 2016. Available from: http://repositorio.ufpe.br/handle/123456789/19535

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

7. Secardin, Lise. Modélisation des néoplasmes myéloprolifératifs grâce aux cellules souches induites à la pluripotence (IPSC) : Modeling of myeloproliferative neoplasms thanks to an induced pluripotent stem cell model (IPSC).

Degree: Docteur es, Aspects moléculaires et cellulaires de la biologie. Hématologie et oncologie, 2016, Sorbonne Paris Cité

URL: http://www.theses.fr/2016USPCC313

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Les néoplasmes myéloprolifératifs (NMP) sont hémopathies malignes aboutissant à la surproduction d'une ou plusieurs lignées myéloïdes. Elles sont dues à l'acquisition de mutations sur l'axe… (more)

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Les néoplasmes myéloprolifératifs (NMP) sont hémopathies malignes aboutissant à la surproduction d'une ou plusieurs lignées myéloïdes. Elles sont dues à l'acquisition de mutations sur l'axe de signalisation MPL/JAK2 incluant des mutations de JAK2V617F, de MPL et plus récemment de la calréticuline (CALR), dont les deux principales sont CALRdel52 et CALRins5. Ces mutations de signalisations peuvent être accompagnées de mutations de l'épigénétique, les plus importantes étant des mutations dans TET2. Le but de cette thèse était d'étudier le rôle des mutations de TET2 et de la calrdel52 dans les NMP grâce à une technologie de cellules souches induites à la pluripotence (IPSC). Dans la première partie j'ai pu démontrer que TET2 joue un rôle dans le processus de reprogrammation, vraisemblablement de manière indépendante de son activité catalytique. Dans la seconde partie, j'ai démontré que CALRdel52 joue un rôle dans les MPN en provoquant une hypersensibilité et une pousse indépendante de la TPO des progéniteurs mégakaryocytaires ainsi qu'une hyperprolifération des mégacaryocytes, liées à l'activation constitutive de stat3 et de ERK. J'ai également démontré une pousse indépendante du GCSF des granulocytes. Ce travail a donc permis de mettre en lumière le rôle du facteur épigénétique TET2 dans le processus de reprogrammation ainsi que le rôle de CALRdel52 dans les MPN dans un contexte d'expression endogène.

Myeloproliferative neoplasms (NMP) are hematological malignancies that lead to an ovrproduction of one or more myeloid lineages. They are driving by mutations in MPLl/jak2 signaling pathway, mainly JAK2V617F, MPL, and more recently calreticulin (CARL), with two main mutations being calrdel52 and calrins5. These signaling mutations are sometimes associated with epigenetic mutations, the major one being in tet2. The objective of my thesis was to study the role of TET2 and CALRdel52 in MPN thanks to an induced pluripotent stem cells (IPSC) model. In the first part i demonstrated the role of TET2 in reprogramming process, probably independently of the catalytic domain. In the second part i demonstrated that CALRdel52 induced a TPO hypersensitivity and a TPO indenpendant growth of the megakaryocytic progenitors as well as a hyperproliferation of the megakaryocytes. This phenotype is associated with a constitutive activation of stat3 and ERK. A G-CSF independent growth of the granulocyte was also demonstrated. In conclusion this work underline the role of an epegenetic factor, TET2, in the reprogramming process and demonstrate the role of CALRdel52in MPN with an endogenous expression model.

Advisors/Committee Members: Plo, Isabelle (thesis director).

Subjects/Keywords: Néoplasmes myéloprolifératifs; JAK/STAT; TET2; IPSC; Myeloproliferative neoplasms; JAK/STAT; TET2; IPSC

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Secardin, L. (2016). Modélisation des néoplasmes myéloprolifératifs grâce aux cellules souches induites à la pluripotence (IPSC) : Modeling of myeloproliferative neoplasms thanks to an induced pluripotent stem cell model (IPSC). (Doctoral Dissertation). Sorbonne Paris Cité. Retrieved from http://www.theses.fr/2016USPCC313

Chicago Manual of Style (16^th Edition):

Secardin, Lise. “Modélisation des néoplasmes myéloprolifératifs grâce aux cellules souches induites à la pluripotence (IPSC) : Modeling of myeloproliferative neoplasms thanks to an induced pluripotent stem cell model (IPSC).” 2016. Doctoral Dissertation, Sorbonne Paris Cité. Accessed January 18, 2021. http://www.theses.fr/2016USPCC313.

MLA Handbook (7^th Edition):

Secardin, Lise. “Modélisation des néoplasmes myéloprolifératifs grâce aux cellules souches induites à la pluripotence (IPSC) : Modeling of myeloproliferative neoplasms thanks to an induced pluripotent stem cell model (IPSC).” 2016. Web. 18 Jan 2021.

Vancouver:

Secardin L. Modélisation des néoplasmes myéloprolifératifs grâce aux cellules souches induites à la pluripotence (IPSC) : Modeling of myeloproliferative neoplasms thanks to an induced pluripotent stem cell model (IPSC). [Internet] [Doctoral dissertation]. Sorbonne Paris Cité; 2016. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2016USPCC313.

Council of Science Editors:

Secardin L. Modélisation des néoplasmes myéloprolifératifs grâce aux cellules souches induites à la pluripotence (IPSC) : Modeling of myeloproliferative neoplasms thanks to an induced pluripotent stem cell model (IPSC). [Doctoral Dissertation]. Sorbonne Paris Cité; 2016. Available from: http://www.theses.fr/2016USPCC313

Université Paris-Sud – Paris XI

8. Ruez, Richard. Mécanotransduction par les cavéoles : rôle dans l'activation de stat3 par l'interferon alpha : Mechannotransduction by the caveolae : a role in the activation of stat3 by the interferon alpha.

Degree: Docteur es, Biologie, 2011, Université Paris-Sud – Paris XI

URL: http://www.theses.fr/2011PA112232

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Hypothèse : Notre équipe étudie le rôle, mal connu, du trafic membranaire dans le contrôle de l’activation de la voie de signalisation JAK/STAT par les… (more)

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Hypothèse : Notre équipe étudie le rôle, mal connu, du trafic membranaire dans le contrôle de l’activation de la voie de signalisation JAK/STAT par les interférons (IFN), une voie clé du contrôle des processus cancéreux. La liaison de l’IFN-a à son récepteur IFNAR active les kinases JAK1 et TYK2 puis des transducteurs de signal comme STAT1, antiprolifératif, ou STAT3, qui a un pouvoir oncogénique. Le laboratoire a démontré récemment que le trafic membranaire d’IFNAR détermine la spécificité du signal des différents IFNs.L’objet de cette thèse est l’étude du rôle des cavéoles dans ce contrôle. Les cavéoles sont des invaginations membranaires enrichies en cholestérol et glycosphingolipides, formées par l’oligomérisation de la cavéoline1 (Cav1). Les cavéoles ou le gène CAV1 ont souvent été associés à la progression tumorale, notamment des cellules mammaires, mais ce rôle reste énigmatique et controversé. Le fait que IFNAR ait été détecté par biochimie dans des fractions de membrane enrichies en cholestérol et positives pour la cavéoline-1 chez la souris et le fait que l’expression du gène CAV1 ait été corrélée à l’action antitumorale de l’IFNa nous ont conduit à étudier le rôle des cavéoles dans l’action antitumorale des IFNs.Résultats: Le rôle putatif des cavéoles sur le contrôle de la voie JAK/STAT a été étudié dans des cellules murines MLEC n’exprimant pas Cav1 et dans des lignées humaines par interférence ARN contre Cav1. Nous avons pu démontrer que la présence de Cav1 régule de manière opposée deux étapes de la voie de signalisation de STAT3 activée par l’IFN-a. Par contre, ni l’activation de STAT1 par l’IFN-a ni celle de STAT3 par les autres IFNs ne nécessitent Cav1. Parallèlement, le laboratoire a montré que les cavéoles jouent un rôle capital dans la réponse cellulaire aux stress mécaniques en se dépliant lors d’un étirement membranaire, ce qui amortit la tension membranaire. Nous montrons qu’un tel stress mécanique par étirement module spécifiquement la signalisation de STAT3 par l’IFN-a d’une manière dépendante de Cav1 dans les cellules MLEC, suggérant pour la première fois un rôle de STAT3 et de l’IFN-a dans la mécanotransduction dépendante des cavéoles. Ce résultat permet aussi de relier les contraintes mécaniques présentes dans la masse tumorale et leur effet sur la progression tumorale. Perspectives : Les IFNs et la voie JAK/STAT sont bien caractérisés pour leur action antiproliférative, mais si l’IFN-a est utilisé en thérapeutique oncologique, les mécanismes de l’effet antitumoral sont mal connus. Nos résultats impliquent pour la première fois les cavéoles dans l’activation sélective du proto-oncogène STAT3 par l’IFN-a et proposent STAT3 comme un des nouveaux acteurs de la mécanotransduction par les cavéoles. Elucider les mécanismes moléculaires mis en jeu dans ces deux fonctions inédites des cavéoles devrait permettre d’identifier de nouvelles cibles thérapeutiques dans la progression tumorale.

Hypothesis: Our team studies the poorly investigated role of membrane trafficking in the control of the…

Advisors/Committee Members: Lamaze, Christophe (thesis director).

Subjects/Keywords: Signalisation; Interféron; Cavéole; Cavéoline; JAK/STAT; Mecanotransduction; Signaling; Interferon; Caveolae; Caveolin; JAK/STAT; Mechanotransduction

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ruez, R. (2011). Mécanotransduction par les cavéoles : rôle dans l'activation de stat3 par l'interferon alpha : Mechannotransduction by the caveolae : a role in the activation of stat3 by the interferon alpha. (Doctoral Dissertation). Université Paris-Sud – Paris XI. Retrieved from http://www.theses.fr/2011PA112232

Chicago Manual of Style (16^th Edition):

Ruez, Richard. “Mécanotransduction par les cavéoles : rôle dans l'activation de stat3 par l'interferon alpha : Mechannotransduction by the caveolae : a role in the activation of stat3 by the interferon alpha.” 2011. Doctoral Dissertation, Université Paris-Sud – Paris XI. Accessed January 18, 2021. http://www.theses.fr/2011PA112232.

MLA Handbook (7^th Edition):

Ruez, Richard. “Mécanotransduction par les cavéoles : rôle dans l'activation de stat3 par l'interferon alpha : Mechannotransduction by the caveolae : a role in the activation of stat3 by the interferon alpha.” 2011. Web. 18 Jan 2021.

Vancouver:

Ruez R. Mécanotransduction par les cavéoles : rôle dans l'activation de stat3 par l'interferon alpha : Mechannotransduction by the caveolae : a role in the activation of stat3 by the interferon alpha. [Internet] [Doctoral dissertation]. Université Paris-Sud – Paris XI; 2011. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2011PA112232.

Council of Science Editors:

Ruez R. Mécanotransduction par les cavéoles : rôle dans l'activation de stat3 par l'interferon alpha : Mechannotransduction by the caveolae : a role in the activation of stat3 by the interferon alpha. [Doctoral Dissertation]. Université Paris-Sud – Paris XI; 2011. Available from: http://www.theses.fr/2011PA112232

9. Jark, Paulo César [UNESP]. Estudo da via jak2/stat3 e de seus inibidores em linfomas multicêntricos difusos de grandes células B caninos.

Degree: 2016, Universidade Estadual Paulista

URL: http://hdl.handle.net/11449/146685

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A via Janus Kinase (JAK) e do transdutor de sinal e ativador de transcrição (STAT) desempenham papéis importantes na patogênese de neoplasias hematopoiéticas. A ativação… (more)

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A via Janus Kinase (JAK) e do transdutor de sinal e ativador de transcrição (STAT) desempenham papéis importantes na patogênese de neoplasias hematopoiéticas. A ativação da via JAK2/STAT3 promove o crescimento e sobrevivência celular em uma variedade de linfomas humanos. Há uma necessidade de compreender a participação da via JAK2/STAT3 em linfomas caninos difusos de grandes células B e do potencial terapêutico dos inibidores de JAK no tratamento dessa doença. O objetivo do presente estudo foi avaliar a expressão de JAK2-STAT3 em linfomas difusos de grandes células B e o impacto do uso de inibidores de JAK2 como AZD1480 e CYT387 no crescimento in vitro dessa linhagem tumoral. Foi realizada técnica de imuno-histoquímica com os anticorpos anti-STAT3 e anti-STAT3 fosforilado (p-STAT3) em linfonodos acometidos por linfoma difuso de grandes células B e comparado à linfonodos normais e reativos. Para avaliação do efeito terapêutico dos inibidores de JAK2 (AZD1480 e CYT387) foi realizado ensaio de viabilidade celular pelo método de azul de tripan utilizando linhagens celulares de linfoma difuso de grandes células B (CLBL-1) e análise de apoptose por citometria de fluxo utilizando o sistema Annexin V. Houve aumento significativo na expressão de STAT3 e p-STAT3 em linfomas difusos de grandes células B em comparação com linfonodos normais. Ambos os fármacos inibiram o crescimento celular em proporções dependentes da dose administrada e houve um aumento significativo nas taxas de apoptose das células tratadas com inibidores de JAK-2 em comparação ao grupo controle tratado com DMSO. Este é o primeiro estudo a avaliar a via JAK2/STAT3 em linfomas difusos de grandes céluslas B canino e esses dados permitem compreender e explorar o potencial terapêutico dos inibidores de JAK permitindo estudos futuros da eficácia clínica desses fármacos na oncologia veterinária

The Janus Kinase (JAK) and signal transducer and activator of transcription (STAT) pathway play important roles in the pathogenesis of hematologic malignancies. Activated JAK2-STAT3 signaling pathway promotes the growth and survival of a variety of lymphomas in human. There is a great demand for understanding JAK-STAT pathway in canine diffuse large B cell lymphoma (DLBCLs) and evaluating the therapeutic potential of JAK inhibitors. Our study aims to evaluate the expression of JAK2-STAT3 pathway in canine DLBCLs and to assess the impact of AZD1480 and CYT387, two novel JAK inhibitors, on canine DLBCL cell growth. Immunohistochemistry was performed in canine DLBCLs, normal and reactive lymph nodes with primary antibodies against STAT3 and phosphorylated STAT3 (p-STAT3). To evaluate the therapeutic effect of novel JAK inhibitors, canine DLBCL cell line CLBL-1 was treated with either AZD1480 or CYT387 and trypan blue viability assay was performed post treatment. There was a significant increase in expression of STAT3 and pSTAT3 in canine DLBCLs compared with the normal lymph node. Both AZD1480 and CYT387 inhibited canine DLBCL cells in a dose dependent manner. This is the…

Advisors/Committee Members: Tinucci Costa, Mirela [UNESP], Universidade Estadual Paulista (UNESP).

Subjects/Keywords: Oncologia; Neoplasias hematopoiéticas; Cães; Terapias alvo; Inibidores de JAK; Oncology; Hematopoietic neoplasia; Dogs; Target therapy; JAK inhibitors

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Jark, P. C. [. (2016). Estudo da via jak2/stat3 e de seus inibidores em linfomas multicêntricos difusos de grandes células B caninos. (Thesis). Universidade Estadual Paulista. Retrieved from http://hdl.handle.net/11449/146685

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Jark, Paulo César [UNESP]. “Estudo da via jak2/stat3 e de seus inibidores em linfomas multicêntricos difusos de grandes células B caninos.” 2016. Thesis, Universidade Estadual Paulista. Accessed January 18, 2021. http://hdl.handle.net/11449/146685.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Jark, Paulo César [UNESP]. “Estudo da via jak2/stat3 e de seus inibidores em linfomas multicêntricos difusos de grandes células B caninos.” 2016. Web. 18 Jan 2021.

Vancouver:

Jark PC[. Estudo da via jak2/stat3 e de seus inibidores em linfomas multicêntricos difusos de grandes células B caninos. [Internet] [Thesis]. Universidade Estadual Paulista; 2016. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/11449/146685.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Jark PC[. Estudo da via jak2/stat3 e de seus inibidores em linfomas multicêntricos difusos de grandes células B caninos. [Thesis]. Universidade Estadual Paulista; 2016. Available from: http://hdl.handle.net/11449/146685

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

10. Torres Espinosa, Alba Yurani. Lien entre signalisation JAK/STAT, remodelage cellulaire et extrusion d’un groupe de cellules épithéliales dans l’ovaire de drosophile : Link Between JAK/STAT signaling, cell remodeling and extrusion from the follicular epithelium in the Drosophila ovary.

Degree: Docteur es, Sciences de la vie et de la santé, 2016, Université Paris-Saclay (ComUE)

URL: http://www.theses.fr/2016SACLS558

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Les cellules épithéliales changent en forme et en nombre au cours de divers processus morphogénétiques pendant le développement. La dynamique du réseau d’acto-myosine en interaction… (more)

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Les cellules épithéliales changent en forme et en nombre au cours de divers processus morphogénétiques pendant le développement. La dynamique du réseau d’acto-myosine en interaction directe avec les jonctions adhérentes (JA) est à la base de ces mouvements cellulaires. Cependant, les mécanismes qui régulent cette dynamique cellulaire et moléculaire dans l’espace et le temps sont peu étudiés. Durant les stades précoces de l’ovogenèse chez la drosophile, le follicule ovarien est une sphère composée d'un cyste germinal recouvert d'un épithélium folliculaire monocouche d'origine somatique. Aux pôles de cette structure, un groupe de cellules, les Cellules Polaires (CP), sont produites en excès (3-6 cellules) au début de l'ovogenèse, et ensuite subissent une mort cellulaire programmée apoptotique entre les stades 2 et 4 de l’ovogenèse. De cette façon, à partir du stade 5 tous les pôles contiendront 2CP. Les CP sont l’unique source de sécrétion du ligand de la voie de signalisation JAK/STAT, Unpaired. Notre équipe a démontré que l’activation autonome et non-autonome cellulaire de la voie JAK/STAT est nécessaire pour l'apoptose développementale des CP. Grâce à l’utilisation de l’imagerie confocale en temps réel ainsi que sur des tissus fixés, j’ai établi une séquence d’évènements stéréotypés qui a lieu pendant l’élimination des CP surnuméraires. Trois phases ont été identifiées dans cette séquence: 1) une phase lente de remodelage cellulaire dépendante de la voie de signalisation JAK/STAT au cours de laquelle chaque CP à être éliminée est totalement enveloppée par les CP voisines (plus de 7h) ; 2) une phase d’activation de la cascade canonique de l’apoptose, commençant lorsque la PC est entièrement enveloppée, suivie d’un détachement puis d’une extrusion latérale des corps apoptotiques (1h) ; et 3) une phase de phagocytose des corps apoptotiques par les Cellules Folliculaires (CF) voisines (plus de 5h). Ensuite, en utilisant une approche gènes candidats, j’ai effectué des perturbations génétiques de la Myosine, de la Cadhérine et de différents régulateurs de l’Actine dans les CF et/ou dans les CP, ainsi que des analyses de la dynamique de certaines de ces molécules. Ces expériences m’ont permis de déterminer que la fonction de ces molécules est nécessaire dans les CF pour le processus d’élimination des CP surnuméraires. Finalement un lien entre la signalisation JAK/STAT et la dynamique de la Myosine a été mis en évidence.

Epithelial cells change in shape and number over the various morphogenetic processes occurring during development. The dynamics of the acto-myosin network in direct interaction with adherens junctions is the basis of these cell movements. However, the mechanisms regulating these cellular and molecular dynamics in space and time have not been much studied. During the early stages of oogenesis in Drosophila, the ovarian follicle is a sphere composed of a germline cyst surrounded by a mono-layered follicular epithelium of somatic origin. At the poles of this structure, a group of cells, the Polar Cells…

Advisors/Committee Members: Agnès, François (thesis director), Pret, Anne-Marie (thesis director).

Subjects/Keywords: Morphogenèse; Extrusion épithéliale; Signalisation JAK/STAT; Acto-Myosine; Apoptose; Morphogenesis; Epithelial cell extrusion; JAK/STAT signaling; Acto-Myosin; Apoptosis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Torres Espinosa, A. Y. (2016). Lien entre signalisation JAK/STAT, remodelage cellulaire et extrusion d’un groupe de cellules épithéliales dans l’ovaire de drosophile : Link Between JAK/STAT signaling, cell remodeling and extrusion from the follicular epithelium in the Drosophila ovary. (Doctoral Dissertation). Université Paris-Saclay (ComUE). Retrieved from http://www.theses.fr/2016SACLS558

Chicago Manual of Style (16^th Edition):

Torres Espinosa, Alba Yurani. “Lien entre signalisation JAK/STAT, remodelage cellulaire et extrusion d’un groupe de cellules épithéliales dans l’ovaire de drosophile : Link Between JAK/STAT signaling, cell remodeling and extrusion from the follicular epithelium in the Drosophila ovary.” 2016. Doctoral Dissertation, Université Paris-Saclay (ComUE). Accessed January 18, 2021. http://www.theses.fr/2016SACLS558.

MLA Handbook (7^th Edition):

Torres Espinosa, Alba Yurani. “Lien entre signalisation JAK/STAT, remodelage cellulaire et extrusion d’un groupe de cellules épithéliales dans l’ovaire de drosophile : Link Between JAK/STAT signaling, cell remodeling and extrusion from the follicular epithelium in the Drosophila ovary.” 2016. Web. 18 Jan 2021.

Vancouver:

Torres Espinosa AY. Lien entre signalisation JAK/STAT, remodelage cellulaire et extrusion d’un groupe de cellules épithéliales dans l’ovaire de drosophile : Link Between JAK/STAT signaling, cell remodeling and extrusion from the follicular epithelium in the Drosophila ovary. [Internet] [Doctoral dissertation]. Université Paris-Saclay (ComUE); 2016. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2016SACLS558.

Council of Science Editors:

Torres Espinosa AY. Lien entre signalisation JAK/STAT, remodelage cellulaire et extrusion d’un groupe de cellules épithéliales dans l’ovaire de drosophile : Link Between JAK/STAT signaling, cell remodeling and extrusion from the follicular epithelium in the Drosophila ovary. [Doctoral Dissertation]. Université Paris-Saclay (ComUE); 2016. Available from: http://www.theses.fr/2016SACLS558

11. Bazzi, Wael. Une nouvelle cascade régulant l'hématopoïèse et la réponse inflammatoire chez la drosophile : A novel cascade controlling hematopoiesis and the inflammatory response in flies.

Degree: Docteur es, Génétique, biologie moléculaire et cellulaire, 2017, Université de Strasbourg

URL: http://www.theses.fr/2017STRAJ043

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Les cellules immunitaires provenant des deux vagues hématopoïétiques jouent des rôles distincts dans la réponse immunitaire, ce qui pose la question d’une potentielle communication entre… (more)

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Les cellules immunitaires provenant des deux vagues hématopoïétiques jouent des rôles distincts dans la réponse immunitaire, ce qui pose la question d’une potentielle communication entre les deux vagues d’hématopoïèse. De plus, la réponse immunitaire joue un rôle primordial dans la progression des tumeurs. Les cascades inflammatoires telles que la voie JAK/STAT et la voie Toll régulent l’hématopoïèse et les mutations affectant ces voies sont associées à des défauts hématopoïétiques et au développement de cancer du sang chez l’humain. Les deux voies de signalisation sont conservées au cours de l’évolution. La voie Toll a notamment été découverte chez la drosophile. Comme chez les mammifères, les mutations dans ces cascades produisent chez la larve des tumeurs des cellules du « sang » appelées tumeurs mélanotiques qui sont dues à la prolifération et à la présence d’hémocytes à l’état inflammatoire qui s’agrègent et forment des masses noires mélanisées. Au cours de mon doctorat, j’ai caractérisé l’impact de Gcm, le seul facteur de transcription spécifique de l’hématopoïèse primitive, sur la réponse immunitaire innée et l’activation de l’inflammation. Je me suis concentré sur les voies Toll et JAK/STAT en utilisant le modèle de la drosophile. J’ai pu montrer que Gcm inhibe la formation des tumeurs mélanotiques provoquées par l’activation constitutive de l’une ou l’autre voie. Gcm agit en activant l’expression d’inhibiteurs de chacune des deux voies. De plus, mes données montrent pour la première fois l’interaction entre les vagues d’hématopoïèses primitive et définitive, une interaction qui est nécessaire pour monter une réponse inflammatoire efficace. Dans ce système, Gcm inhibe la sécrétion de cytokines pro-inflammatoire Upd2 et Upd3 des hémocytes embryonnaires. Mes résultats indiquent également que Gcm a un impact sur l’expression de gènes mitochondriaux dans un fond génétique qui conduit au développement de tumeurs mélanotiques et à un état inflammatoire. Enfin, j’ai transposé mes résultats à un système mammifère en montrant que chez la souris, Gcm induit l’expression d’inhibiteur de la voie JAK/STAT dans une lignée cellulaire leucémique humaine. Pour conclure, mes données mettent en évidence l’importance de la communication entre les deux vagues d’hématopoïèse dans le système immunitaire et montrent qu’une voie de régulation développementale régule la capacité du système à répondre à l’inflammation.

Immune cells originating from different hematopoietic waves play role in mounting an efficient immune response, which raises the aspect of communication between distinct waves. In addition, immune responses have pivotal roles in modulating tumor progression. Inflammatory cascades, such as the JAK/STAT and Toll pathways are also known to regulate hematopoiesis and mutations in either of them are associated with hematopoietic defects and blood cancers in humans. Both pathways are highly conserved in evolution and interestingly, the Toll cascade was initially discovered in Drosophila. Like in mammals, mutations within…

Advisors/Committee Members: Giangrande, Angela (thesis director).

Subjects/Keywords: Gcm; Inflammation; JAK/STAT; Toll; Tumeurs mélanotiques; Drosophile; Gcm; Inflammation; JAK/STAT; Toll; Melanotic tumors; Drosophila; 572.8; 616.99

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bazzi, W. (2017). Une nouvelle cascade régulant l'hématopoïèse et la réponse inflammatoire chez la drosophile : A novel cascade controlling hematopoiesis and the inflammatory response in flies. (Doctoral Dissertation). Université de Strasbourg. Retrieved from http://www.theses.fr/2017STRAJ043

Chicago Manual of Style (16^th Edition):

Bazzi, Wael. “Une nouvelle cascade régulant l'hématopoïèse et la réponse inflammatoire chez la drosophile : A novel cascade controlling hematopoiesis and the inflammatory response in flies.” 2017. Doctoral Dissertation, Université de Strasbourg. Accessed January 18, 2021. http://www.theses.fr/2017STRAJ043.

MLA Handbook (7^th Edition):

Bazzi, Wael. “Une nouvelle cascade régulant l'hématopoïèse et la réponse inflammatoire chez la drosophile : A novel cascade controlling hematopoiesis and the inflammatory response in flies.” 2017. Web. 18 Jan 2021.

Vancouver:

Bazzi W. Une nouvelle cascade régulant l'hématopoïèse et la réponse inflammatoire chez la drosophile : A novel cascade controlling hematopoiesis and the inflammatory response in flies. [Internet] [Doctoral dissertation]. Université de Strasbourg; 2017. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2017STRAJ043.

Council of Science Editors:

Bazzi W. Une nouvelle cascade régulant l'hématopoïèse et la réponse inflammatoire chez la drosophile : A novel cascade controlling hematopoiesis and the inflammatory response in flies. [Doctoral Dissertation]. Université de Strasbourg; 2017. Available from: http://www.theses.fr/2017STRAJ043

12. Nascimento, Augusto Santana [UNESP]. Mecanismos moleculares envolvidos com a resistência química de células tumorais de mama.

Degree: 2017, Universidade Estadual Paulista

URL: http://hdl.handle.net/11449/148592

► Embora algum progresso tenha sido alcançado nos últimos anos, ainda são necessários estudos capazes de desvendar os mecanismos moleculares envolvidos com o fenótipo de resistência… (more)

▼ Embora algum progresso tenha sido alcançado nos últimos anos, ainda são necessários estudos capazes de desvendar os mecanismos moleculares envolvidos com o fenótipo de resistência a múltiplas drogas (MDR) em células tumorais. Com esta finalidade, estabelecemos o perfil quinômico (através do microarranjo de peptídeos, PepChip) das linhagens MCF7 e MCF7Res, fenótipo parental e resistente respectivamente, de células de câncer de mama. Os resultados obtidos pelo microarranjo de peptídeos e posteriormente, validados por western blotting, apontaram o envolvimento da via de sinalização Jak-Stat e isoformas de PKC no processo de resistência das células de câncer de mama. Além disso, mostramos envolvimento de p42/44-mapk, Ras e um aumento na expressão de MMP-9. Estes resultados mostram o potencial agressivo destas células resistentes, visto que estas vias estão envolvidas em mecanismos responsáveis pela proliferação e invasão celular. Como as proteínas Jak1 e Jak2 mostraram-se envolvidas, decidimos avaliar níveis de fosforilação de Stats 1, 2, 3, 5 e 6 e mostramos que todas estavam up-fosforiladas nas células resistentes. Baseado nestes resultados, decidimos avaliar através de um ensaio funcional, o papel de Jak2 no fenótipo resistente e, desta forma, avaliamos a viabilidade das células MCF7Res em pré-tratamento com 2 concentrações subtóxicas do inibidor de Jak2 (5µM e 10µM) e nossos resultados claramente mostraram que, inibindo Jak2, as células MCF7Res ficam mais sensíveis a daunorrubicina, aumentando a taxa de morte celular frente à resposta ao quimioterápico. Baseado nos resultados obtidos pelo fosfoproteoma concluímos que o fenótipo MDR envolve metabolismo específico em células tumorais de mama, onde isoformas de PKCs e sinalização Jak-Stat exercem função de destaque. Assim, estes dados apontam o potencial uso de inibidores de Jak2 como estratégia para o tratamento de pacientes não responsivos a terapias convencionais. Advisors/Committee Members: Zambuzzi, Willian Fernando [UNESP], Universidade Estadual Paulista (UNESP).

Subjects/Keywords: Câncer de mama; Resistência; PepChip; PKC; Jak-Stat

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APA (6^th Edition):

Nascimento, A. S. [. (2017). Mecanismos moleculares envolvidos com a resistência química de células tumorais de mama. (Thesis). Universidade Estadual Paulista. Retrieved from http://hdl.handle.net/11449/148592

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Nascimento, Augusto Santana [UNESP]. “Mecanismos moleculares envolvidos com a resistência química de células tumorais de mama.” 2017. Thesis, Universidade Estadual Paulista. Accessed January 18, 2021. http://hdl.handle.net/11449/148592.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Nascimento, Augusto Santana [UNESP]. “Mecanismos moleculares envolvidos com a resistência química de células tumorais de mama.” 2017. Web. 18 Jan 2021.

Vancouver:

Nascimento AS[. Mecanismos moleculares envolvidos com a resistência química de células tumorais de mama. [Internet] [Thesis]. Universidade Estadual Paulista; 2017. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/11449/148592.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Nascimento AS[. Mecanismos moleculares envolvidos com a resistência química de células tumorais de mama. [Thesis]. Universidade Estadual Paulista; 2017. Available from: http://hdl.handle.net/11449/148592

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Ottawa

13. Davis, Colin. Comparative Study of Colon Cancer Subclones Uncovers Potential Roles for AKAP7 and TP53RK in the Antiviral Response.

Degree: 2016, University of Ottawa

URL: http://hdl.handle.net/10393/34183

► Tumour heterogeneity is a key hurdle for the effective treatment of cancer using oncolytic viruses (OVs). A better understanding of the pathways involved in delineating… (more)

Subjects/Keywords: Oncolytic Virus; Antiviral; CT26; Clone; Heterogeneity; JAK-STAT; Viral Sensitivity

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APA (6^th Edition):

Davis, C. (2016). Comparative Study of Colon Cancer Subclones Uncovers Potential Roles for AKAP7 and TP53RK in the Antiviral Response. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/34183

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Davis, Colin. “Comparative Study of Colon Cancer Subclones Uncovers Potential Roles for AKAP7 and TP53RK in the Antiviral Response. ” 2016. Thesis, University of Ottawa. Accessed January 18, 2021. http://hdl.handle.net/10393/34183.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Davis, Colin. “Comparative Study of Colon Cancer Subclones Uncovers Potential Roles for AKAP7 and TP53RK in the Antiviral Response. ” 2016. Web. 18 Jan 2021.

Vancouver:

Davis C. Comparative Study of Colon Cancer Subclones Uncovers Potential Roles for AKAP7 and TP53RK in the Antiviral Response. [Internet] [Thesis]. University of Ottawa; 2016. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10393/34183.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Davis C. Comparative Study of Colon Cancer Subclones Uncovers Potential Roles for AKAP7 and TP53RK in the Antiviral Response. [Thesis]. University of Ottawa; 2016. Available from: http://hdl.handle.net/10393/34183

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Tampere University

14. Hammarén, Henrik. Intramolecular regulation of Janus kinases .

Degree: 2017, Tampere University

URL: https://trepo.tuni.fi/handle/10024/102330

► Janus-kinaasit (JAKit) ovat ei-reseptorisia tyrosiinikinaaseja, jotka välittävät yli 60 sytokiinin viestejä soluissa. Nämä viestit säätelevät lukuisia biologisia tapahtumia, kuten immuunijärjestelmän toimintaa, hematopoieesia, aineenvaihduntaa sekä kehitystä.… (more)

▼ Janus-kinaasit (JAKit) ovat ei-reseptorisia tyrosiinikinaaseja, jotka välittävät yli 60 sytokiinin viestejä soluissa. Nämä viestit säätelevät lukuisia biologisia tapahtumia, kuten immuunijärjestelmän toimintaa, hematopoieesia, aineenvaihduntaa sekä kehitystä. JAKit ovat monidomeenisia proteeineja, joissa viestivää, aktiivista tyrosiinikinaasidomeenia (JH1) edeltää nk. pseudokinaasidomeeni (JH2). JH2 on ensisijaisen tärkeä JAK-aktiivisuuden säätelyssä. Domeenista onkin löydetty lukuisia kliinisesti merkittäviä mutaatioita, kuten autosomaalisia JAK2-mutaatioita, jotka aiheuttavat ligandiriippumatonta JAK-aktivaatiota ja siten johtavat hematopoieettisiin maligniteetteihin. Tässä työssä esitellyissä tutkimuksissa selvitettiin JH2:n sekä sen mutaatioiden toimintaa JAK-säätelyssä. Tutkimuksissa havaittiin, että kaikissa JAK JH2:ssa on toiminnallinen nukleotidinsitomistasku, joka kykenee sitomaan ATP:ta ja pienmolekyylisiä inhibiittoreita. Tärkeimpänä löydöksenä havaittiin, että ATP:n sitoutumisen estäminen JAK2 JH2:n ATP-sitomistaskuun alentaa ligandiriippumatonta JAK2-aktivaatiota. Nämä havainnot osoittavat, että JAK2 JH2 on mahdollinen lääkekohde kohdennettujen JAK-inhibiittoreiden kehittämiselle. Tällaiset inhibiittorit, jotka estäisivät kohdennetusti mutatoituneen (muttei villityyppisen) JAKin toimintaa, olisivat merkittävä parannus verrattuna nykyisiin JAK-estäjiin, jotka eivät kykene erottelemaan villityyppisen ja mutatoituneen JAKin välillä, eivätkä siten pysty parantamaan tautia. Tutkimuksissa kehitettiin yhteistyöprojektina myös molekyylimalli JH2:n toiminnasta JH1:n aktiivisuuden säätelijänä. JH2–JH1-malli selittää useimpien tunnettujen kliinisten JAK2-mutaatioiden toiminnan molekyylitasolla. Lisäksi suoritettiin systemaattinen analyysi JAK2-mutaatioista, jotka voivat estää tautia aiheuttavan JAK2-hyperaktivaation. Tämä analyysi tarkentaa ymmärrystämme JAKien toiminnasta sytokiinivälitteisessä sekä sytokiineista riippumattomassa JAK-aktivaatiossa ja samalla tunnistaa aiemmin tuntemattoman JAK2 JH2 rajapinnan, joka on välttämätön interferoni-γ signaloinnille.; Janus kinases (JAKs) are non-receptor tyrosine kinases that mediate signalling of around sixty different cytokines governing various biological processes from the regulation of the immune system, to control of haematopoiesis, metabolism, and development. JAKs are multidomain proteins, in which the tyrosine kinase domain (JH1) is preceded by a pseudokinase domain (JH2). JH2 has critical regulatory functions and is a hotspot for many known oncogenic driver mutations. These mutations, which cause ligand-independent JAK activation, underlie various diseases—most notably haematopoietic malignancies caused by somatic JAK2 JH2 mutations. In the work presented here, we analysed the functions of JH2 and its mutations in the regulation of JAK activity. We found that all JAK JH2s have functional nucleotide-binding sites accessible to ATP and small molecule inhibitors. Most importantly, we found that disruption of ATP binding to JAK2 JH2 suppresses ligand-independent…

Subjects/Keywords: kinaasi ; JAK ; pseudokinaasi ; myeloproliferatiivinen neoplasia ; sytokiini ; kinase ; pseudokinase ; myeloproliferative neoplasm ; cytokine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hammarén, H. (2017). Intramolecular regulation of Janus kinases . (Doctoral Dissertation). Tampere University. Retrieved from https://trepo.tuni.fi/handle/10024/102330

Chicago Manual of Style (16^th Edition):

Hammarén, Henrik. “Intramolecular regulation of Janus kinases .” 2017. Doctoral Dissertation, Tampere University. Accessed January 18, 2021. https://trepo.tuni.fi/handle/10024/102330.

MLA Handbook (7^th Edition):

Hammarén, Henrik. “Intramolecular regulation of Janus kinases .” 2017. Web. 18 Jan 2021.

Vancouver:

Hammarén H. Intramolecular regulation of Janus kinases . [Internet] [Doctoral dissertation]. Tampere University; 2017. [cited 2021 Jan 18]. Available from: https://trepo.tuni.fi/handle/10024/102330.

Council of Science Editors:

Hammarén H. Intramolecular regulation of Janus kinases . [Doctoral Dissertation]. Tampere University; 2017. Available from: https://trepo.tuni.fi/handle/10024/102330

15. ウベツ, ギザチョーイスモー. High STAT4 Expression is a Better Prognostic Indicatorin Patients with Hepatocellular Carcinoma After Hepatectomy : STAT4高発現は、肝細胞癌切除症例において予後良好因子である.

Degree: 博士（医学）, 2016, Tokushima University / 徳島大学

URL: http://repo.lib.tokushima-u.ac.jp/109697

Subjects/Keywords: 肝臓癌; STAT4; JAK

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APA (6^th Edition):

ウベツ, �. �. (2016). High STAT4 Expression is a Better Prognostic Indicatorin Patients with Hepatocellular Carcinoma After Hepatectomy : STAT4高発現は、肝細胞癌切除症例において予後良好因子である. (Thesis). Tokushima University / 徳島大学. Retrieved from http://repo.lib.tokushima-u.ac.jp/109697

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

ウベツ, ギザチョーイスモー. “High STAT4 Expression is a Better Prognostic Indicatorin Patients with Hepatocellular Carcinoma After Hepatectomy : STAT4高発現は、肝細胞癌切除症例において予後良好因子である.” 2016. Thesis, Tokushima University / 徳島大学. Accessed January 18, 2021. http://repo.lib.tokushima-u.ac.jp/109697.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

ウベツ, ギザチョーイスモー. “High STAT4 Expression is a Better Prognostic Indicatorin Patients with Hepatocellular Carcinoma After Hepatectomy : STAT4高発現は、肝細胞癌切除症例において予後良好因子である.” 2016. Web. 18 Jan 2021.

Vancouver:

ウベツ ��. High STAT4 Expression is a Better Prognostic Indicatorin Patients with Hepatocellular Carcinoma After Hepatectomy : STAT4高発現は、肝細胞癌切除症例において予後良好因子である. [Internet] [Thesis]. Tokushima University / 徳島大学; 2016. [cited 2021 Jan 18]. Available from: http://repo.lib.tokushima-u.ac.jp/109697.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

ウベツ ��. High STAT4 Expression is a Better Prognostic Indicatorin Patients with Hepatocellular Carcinoma After Hepatectomy : STAT4高発現は、肝細胞癌切除症例において予後良好因子である. [Thesis]. Tokushima University / 徳島大学; 2016. Available from: http://repo.lib.tokushima-u.ac.jp/109697

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Boston University

16. Hokenson, Kristen Elizabeth. BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons.

Degree: PhD, Pharmacology, 2016, Boston University

URL: http://hdl.handle.net/2144/16740

► Epilepsy is a neurological disorder that causes recurrent and unprovoked seizures due to imbalances in synaptic transmission in distinct regions of the brain. In both… (more)

▼ Epilepsy is a neurological disorder that causes recurrent and unprovoked seizures due to imbalances in synaptic transmission in distinct regions of the brain. In both human patients and animal models of epilepsy, there is a marked increase in brain-derived neurotrophic factor (BDNF), a critical signaling molecule in the brain that contributes to two divergent pathways important to disease pathology: 1) the regulation of type A receptors for the major inhibitory neurotransmitter GABA (GABAARs), and 2) aberrant neurogenesis with ectopic expression of new neurons from progenitor cells that disrupt neural network activity in the hippocampus. The first part of my thesis addresses how neurons regulate levels of α1-containing GABAARs through BDNF signaling at its receptors, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR). I hypothesized and showed that BDNF, working at TrkB, rapidly activates the Janus kinase and signal transducers and activators of transcription (JAK/STAT) pathway in neurons and identified a novel intracellular receptor signaling complex composed of p75NTR and JAK2 that is present in neuronal processes, cell body, and nucleus. Based on this finding, we suggest that an intracellular p75NTR/JAK2 signalsome recruits STAT3, a transcriptional activator of the gene coding for the cAMP inducible early repressor (ICER) that blocks synthesis of α1 subunits reducing synaptic GABAARs in response to status epilepticus. This model is consistent with our collaborative studies that show a JAK2 inhibitor, WP1066, inhibits development of spontaneous seizures in an epilepsy model and my observation that WP1066 degrades JAK2 protein in primary neurons. The second part of my thesis addresses BDNF regulation of the Late SV40 Factor (LSF), a ubiquitous transcription factor that regulates cell cycle progression and survival. I show that BDNF through the mitogen-activated protein kinase pathway selectively phosphorylates LSF at serine 291 (p291LSF) and that p291LSF is present throughout neurogenesis, increases with status epilepticus in the hippocampus, and is highest in structures associated with neurogenesis (such as olfactory bulb and hippocampus when compared to cortex). Taken together, these results suggest LSF may play an important role in neuronal development and potentially in epilepsy, providing an additional target for future therapeutic intervention.

Subjects/Keywords: Neurosciences; BDNF; Epilepsy; GABA; JAK/STAT; LSF; Neurogenesis

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APA (6^th Edition):

Hokenson, K. E. (2016). BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons. (Doctoral Dissertation). Boston University. Retrieved from http://hdl.handle.net/2144/16740

Chicago Manual of Style (16^th Edition):

Hokenson, Kristen Elizabeth. “BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons.” 2016. Doctoral Dissertation, Boston University. Accessed January 18, 2021. http://hdl.handle.net/2144/16740.

MLA Handbook (7^th Edition):

Hokenson, Kristen Elizabeth. “BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons.” 2016. Web. 18 Jan 2021.

Vancouver:

Hokenson KE. BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons. [Internet] [Doctoral dissertation]. Boston University; 2016. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2144/16740.

Council of Science Editors:

Hokenson KE. BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons. [Doctoral Dissertation]. Boston University; 2016. Available from: http://hdl.handle.net/2144/16740

University of Toronto

17. Gupta, Shaan. MicroRNA-17 Targets JAK1 and STAT3 to Inhibit Osteoblast Differentiation.

Degree: 2014, University of Toronto

URL: http://hdl.handle.net/1807/67894

►

MicroRNA-17 (miR-17) was hypothesized to target janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) to inhibit osteogenesis in pre-osteoblast cells.… (more)

Subjects/Keywords: bone formation; JAK-STAT; microRNA; Osteoblast Differentiation; Osteogenesis; osteoporosis; 0307

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APA (6^th Edition):

Gupta, S. (2014). MicroRNA-17 Targets JAK1 and STAT3 to Inhibit Osteoblast Differentiation. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/67894

Chicago Manual of Style (16^th Edition):

Gupta, Shaan. “MicroRNA-17 Targets JAK1 and STAT3 to Inhibit Osteoblast Differentiation.” 2014. Masters Thesis, University of Toronto. Accessed January 18, 2021. http://hdl.handle.net/1807/67894.

MLA Handbook (7^th Edition):

Gupta, Shaan. “MicroRNA-17 Targets JAK1 and STAT3 to Inhibit Osteoblast Differentiation.” 2014. Web. 18 Jan 2021.

Vancouver:

Gupta S. MicroRNA-17 Targets JAK1 and STAT3 to Inhibit Osteoblast Differentiation. [Internet] [Masters thesis]. University of Toronto; 2014. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1807/67894.

Council of Science Editors:

Gupta S. MicroRNA-17 Targets JAK1 and STAT3 to Inhibit Osteoblast Differentiation. [Masters Thesis]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/67894

18. Fernandez, David Jaime. Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes.

Degree: PhD, Biology, 2012, The Catholic University of America

URL: http://hdl.handle.net/1961/etd:388

►

Degree awarded: Ph.D. Biology. The Catholic University of America

The molecular basis for alcohol-induced hepatotoxicity is not well-understood. We sought to further explore a known… (more)

▼

Degree awarded: Ph.D. Biology. The Catholic University of America

The molecular basis for alcohol-induced hepatotoxicity is not well-understood. We sought to further explore a known protein trafficking defect caused by chronic alcohol exposure: receptor internalization from the hepatocyte plasma membrane, and a hypothesized defect in microtubule-dependent nuclear translocation of transcription factors. We hypothesized that both of these defects are caused by ethanol-induced protein hyperacetylation. Previously, we determined that the clathrin-mediated internalization of asialoglycoprotein receptor (ASGP-R) was impaired in ethanol-treated WIF-B cells, whereas the internalization of a glycophosphatidylinositol (GPI)-anchored protein internalized via a caveolae/raft-mediated pathway was not changed. ASGP-R internalization was also impaired by trichostatin-A (TSA), a drug that induces global protein hyperacetylation, providing evidence that hyperacetylation is indeed associated with this defect. We examined a panel of proteins and compounds internalized by different mechanisms in control and ethanol-treated WIF-B cells. Markers known to be internalized via clathrin-mediated endocytosis were impaired, whereas the internalization of markers for caveolae/raft-mediated-, fluid phase-, or non-vesicle-mediated mechanisms was not altered after ethanol exposure. We conclude that clathrin-mediated endocytosis is selectively impaired by ethanol exposure. Previously we found that alcohol exposure led to increased microtubule acetylation and stability in WIF-B cells and livers from ethanol-fed rats. Because dynamic microtubules are known to regulate nuclear translocation of some transcription factors, we examined whether alcohol-induced microtubule acetylation and stability impair nuclear translocation. Representing factors that undergo directed nuclear delivery, we examined the growth hormone-induced translocation of Signal Transducer and Activator of Transcription 5B (STAT5B) and the interleukin 6 (IL-6) -induced translocation of STAT3. Representing factors that are sequestered in the cytoplasm by microtubule attachment until ligand activation, we examined the Transforming Growth Factor-Beta (TGF-Beta) -induced translocation of Smad2/3. Ethanol exposure impaired the translocation of STAT3 and STAT5B, but not Smad2/3. STAT5B translocation was decreased to similar extents by taxol or trichostatin A, agents that promote microtubule acetylation in the absence of alcohol. Thus, the alcohol-induced impairment of STAT nuclear translocation can be explained by increased microtubule acetylation. Only ethanol-treatment impaired STAT5B activation, indicating microtubule acetylation is not important for this process. Together, these results suggest that deacetylase agonists may be effective therapeutics for treating alcoholic liver disease.

Made available in DSpace on 2012-11-01T17:08:13Z (GMT). No. of bitstreams: 1 Fernandez_cua_0043A_10369display.pdf: 4456009 bytes, checksum: e87206ccfadd525162b1f25330528627 (MD5)

Advisors/Committee Members: Tuma, Pamela L (Advisor), Tuma, Pamela L (Other), Golin, John E (Other), Mullins, James M (Other), Barkatt, Aaron (Other), Philip, John (Other).

Subjects/Keywords: Cellular biology; Acetylation; Alcohol; Hepatocytes; Jak-STAT; Microtubules; Smad

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APA (6^th Edition):

Fernandez, D. J. (2012). Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes. (Doctoral Dissertation). The Catholic University of America. Retrieved from http://hdl.handle.net/1961/etd:388

Chicago Manual of Style (16^th Edition):

Fernandez, David Jaime. “Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes.” 2012. Doctoral Dissertation, The Catholic University of America. Accessed January 18, 2021. http://hdl.handle.net/1961/etd:388.

MLA Handbook (7^th Edition):

Fernandez, David Jaime. “Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes.” 2012. Web. 18 Jan 2021.

Vancouver:

Fernandez DJ. Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes. [Internet] [Doctoral dissertation]. The Catholic University of America; 2012. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1961/etd:388.

Council of Science Editors:

Fernandez DJ. Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes. [Doctoral Dissertation]. The Catholic University of America; 2012. Available from: http://hdl.handle.net/1961/etd:388

University of Debrecen

19. Hamar, Attila. A JAK gátlás lehetőségei az arthritisek kezelésében .

Degree: DE – Általános Orvostudományi Kar, University of Debrecen

URL: http://hdl.handle.net/2437/218475

► A JAK-inhibitorok klinikai hatékonyságának és biztonságosságának irodalmi összefoglalója rheumatoid arthritis megbetegedésekben, fókuszpontban a rheumatoid arthritis terápiájában elsőként elfogadott JAK-gátló, a tofacitinib (Xeljanz) készítménnyel. A rheumatoid… (more)

Subjects/Keywords: JAK; rheumatoid arthritis; tofacitinib

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APA (6^th Edition):

Hamar, A. (n.d.). A JAK gátlás lehetőségei az arthritisek kezelésében . (Thesis). University of Debrecen. Retrieved from http://hdl.handle.net/2437/218475

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Hamar, Attila. “A JAK gátlás lehetőségei az arthritisek kezelésében .” Thesis, University of Debrecen. Accessed January 18, 2021. http://hdl.handle.net/2437/218475.

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Hamar, Attila. “A JAK gátlás lehetőségei az arthritisek kezelésében .” Web. 18 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Hamar A. A JAK gátlás lehetőségei az arthritisek kezelésében . [Internet] [Thesis]. University of Debrecen; [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2437/218475.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

Council of Science Editors:

Hamar A. A JAK gátlás lehetőségei az arthritisek kezelésében . [Thesis]. University of Debrecen; Available from: http://hdl.handle.net/2437/218475

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

20. Fernandez, David Jaime. Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes.

Degree: PhD, Biology, 2012, The Catholic University of America

URL: http://hdl.handle.net/1961/13181

►

Degree awarded: Ph.D. Biology. The Catholic University of America

The molecular basis for alcohol-induced hepatotoxicity is not well-understood. We sought to further explore a known… (more)

▼

Degree awarded: Ph.D. Biology. The Catholic University of America

The molecular basis for alcohol-induced hepatotoxicity is not well-understood. We sought to further explore a known protein trafficking defect caused by chronic alcohol exposure: receptor internalization from the hepatocyte plasma membrane, and a hypothesized defect in microtubule-dependent nuclear translocation of transcription factors. We hypothesized that both of these defects are caused by ethanol-induced protein hyperacetylation. Previously, we determined that the clathrin-mediated internalization of asialoglycoprotein receptor (ASGP-R) was impaired in ethanol-treated WIF-B cells, whereas the internalization of a glycophosphatidylinositol (GPI)-anchored protein internalized via a caveolae/raft-mediated pathway was not changed. ASGP-R internalization was also impaired by trichostatin-A (TSA), a drug that induces global protein hyperacetylation, providing evidence that hyperacetylation is indeed associated with this defect. We examined a panel of proteins and compounds internalized by different mechanisms in control and ethanol-treated WIF-B cells. Markers known to be internalized via clathrin-mediated endocytosis were impaired, whereas the internalization of markers for caveolae/raft-mediated-, fluid phase-, or non-vesicle-mediated mechanisms was not altered after ethanol exposure. We conclude that clathrin-mediated endocytosis is selectively impaired by ethanol exposure. Previously we found that alcohol exposure led to increased microtubule acetylation and stability in WIF-B cells and livers from ethanol-fed rats. Because dynamic microtubules are known to regulate nuclear translocation of some transcription factors, we examined whether alcohol-induced microtubule acetylation and stability impair nuclear translocation. Representing factors that undergo directed nuclear delivery, we examined the growth hormone-induced translocation of Signal Transducer and Activator of Transcription 5B (STAT5B) and the interleukin 6 (IL-6) -induced translocation of STAT3. Representing factors that are sequestered in the cytoplasm by microtubule attachment until ligand activation, we examined the Transforming Growth Factor-Beta (TGF-Beta) -induced translocation of Smad2/3. Ethanol exposure impaired the translocation of STAT3 and STAT5B, but not Smad2/3. STAT5B translocation was decreased to similar extents by taxol or trichostatin A, agents that promote microtubule acetylation in the absence of alcohol. Thus, the alcohol-induced impairment of STAT nuclear translocation can be explained by increased microtubule acetylation. Only ethanol-treatment impaired STAT5B activation, indicating microtubule acetylation is not important for this process. Together, these results suggest that deacetylase agonists may be effective therapeutics for treating alcoholic liver disease.

Made available in DSpace on 2012-11-01T17:08:13Z (GMT). No. of bitstreams: 1 Fernandez_cua_0043A_10369display.pdf: 4456009 bytes, checksum: e87206ccfadd525162b1f25330528627 (MD5)

Advisors/Committee Members: Tuma, Pamela L (Advisor), Tuma, Pamela L (Other), Golin, John E (Other), Mullins, James M (Other), Barkatt, Aaron (Other), Philip, John (Other).

Subjects/Keywords: Cellular biology; Acetylation; Alcohol; Hepatocytes; Jak-STAT; Microtubules; Smad

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APA (6^th Edition):

Fernandez, D. J. (2012). Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes. (Doctoral Dissertation). The Catholic University of America. Retrieved from http://hdl.handle.net/1961/13181

Chicago Manual of Style (16^th Edition):

Fernandez, David Jaime. “Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes.” 2012. Doctoral Dissertation, The Catholic University of America. Accessed January 18, 2021. http://hdl.handle.net/1961/13181.

MLA Handbook (7^th Edition):

Fernandez, David Jaime. “Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes.” 2012. Web. 18 Jan 2021.

Vancouver:

Fernandez DJ. Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes. [Internet] [Doctoral dissertation]. The Catholic University of America; 2012. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1961/13181.

Council of Science Editors:

Fernandez DJ. Chronic Alcohol Consumption Impairs Clathrin-Mediated Endocytosis and Microtubule-Dependent Nuclear Translocation in Hepatocytes. [Doctoral Dissertation]. The Catholic University of America; 2012. Available from: http://hdl.handle.net/1961/13181

Columbia University

21. Wang, Etienne Cho Ee. Hair Growth Is Induced by Blockade of Macrophage-derived Oncostatin M and Downstream Jak-stat5 Signaling in Hair Follicle Stem Cells.

Degree: 2018, Columbia University

URL: https://doi.org/10.7916/D8SX7RQN

► Our lab recently described a role for JAK-STAT signaling in the maintenance of quiescence during the murine hair cycle. Research into signaling pathways and cytokines/growth… (more)

Subjects/Keywords: Cytology; Immunology; Biomedical engineering; JAK-STAT pathway; Hair – Growth

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APA (6^th Edition):

Wang, E. C. E. (2018). Hair Growth Is Induced by Blockade of Macrophage-derived Oncostatin M and Downstream Jak-stat5 Signaling in Hair Follicle Stem Cells. (Doctoral Dissertation). Columbia University. Retrieved from https://doi.org/10.7916/D8SX7RQN

Chicago Manual of Style (16^th Edition):

Wang, Etienne Cho Ee. “Hair Growth Is Induced by Blockade of Macrophage-derived Oncostatin M and Downstream Jak-stat5 Signaling in Hair Follicle Stem Cells.” 2018. Doctoral Dissertation, Columbia University. Accessed January 18, 2021. https://doi.org/10.7916/D8SX7RQN.

MLA Handbook (7^th Edition):

Wang, Etienne Cho Ee. “Hair Growth Is Induced by Blockade of Macrophage-derived Oncostatin M and Downstream Jak-stat5 Signaling in Hair Follicle Stem Cells.” 2018. Web. 18 Jan 2021.

Vancouver:

Wang ECE. Hair Growth Is Induced by Blockade of Macrophage-derived Oncostatin M and Downstream Jak-stat5 Signaling in Hair Follicle Stem Cells. [Internet] [Doctoral dissertation]. Columbia University; 2018. [cited 2021 Jan 18]. Available from: https://doi.org/10.7916/D8SX7RQN.

Council of Science Editors:

Wang ECE. Hair Growth Is Induced by Blockade of Macrophage-derived Oncostatin M and Downstream Jak-stat5 Signaling in Hair Follicle Stem Cells. [Doctoral Dissertation]. Columbia University; 2018. Available from: https://doi.org/10.7916/D8SX7RQN

University of Manitoba

22. Mahood, Thomas. Differential innate immunity responses to West Nile virus and bacterial infections in mosquitoes.

Degree: Biological Sciences, 2013, University of Manitoba

URL: http://hdl.handle.net/1993/16594

► Identifying the molecular interactions of pathogens in different mosquito species is critical for understanding how mosquitoes transmit diseases. In this study, the role of the… (more)

Subjects/Keywords: Molecular Biology; Jak-STAT; Aedes aegypti; Culex quinquefasciatus; LPS; Bioinformatics

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APA (6^th Edition):

Mahood, T. (2013). Differential innate immunity responses to West Nile virus and bacterial infections in mosquitoes. (Masters Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/16594

Chicago Manual of Style (16^th Edition):

Mahood, Thomas. “Differential innate immunity responses to West Nile virus and bacterial infections in mosquitoes.” 2013. Masters Thesis, University of Manitoba. Accessed January 18, 2021. http://hdl.handle.net/1993/16594.

MLA Handbook (7^th Edition):

Mahood, Thomas. “Differential innate immunity responses to West Nile virus and bacterial infections in mosquitoes.” 2013. Web. 18 Jan 2021.

Vancouver:

Mahood T. Differential innate immunity responses to West Nile virus and bacterial infections in mosquitoes. [Internet] [Masters thesis]. University of Manitoba; 2013. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1993/16594.

Council of Science Editors:

Mahood T. Differential innate immunity responses to West Nile virus and bacterial infections in mosquitoes. [Masters Thesis]. University of Manitoba; 2013. Available from: http://hdl.handle.net/1993/16594

Université Catholique de Louvain

23. Springuel, Lorraine. Loss of MLH1 expression promotes the acquisition of oncogenic JAK1 and JAK3 mutations that cooperatively increase resistance to JAK inhibitors.

Degree: 2015, Université Catholique de Louvain

URL: http://hdl.handle.net/2078.1/165779

►

Malignant transformation evolves as the outcome of 2 connected processes operating within a population of competing cells: on the one hand, the continuous accumulation of… (more)

▼

Malignant transformation evolves as the outcome of 2 connected processes operating within a population of competing cells: on the one hand, the continuous accumulation of random mutations by individual cells at a rate dictated by the degree of genetic instability and, on the other hand, the simultaneous natural selection acting on the resultant phenotypes. Successive rounds of environmental pressures lead to the emergence of cells that acquired diverse advantageous hallmarks such as growth factor-independent proliferation, mostly driven by constitutively activated signaling cascades to which neoplastic cells develop an addiction that can be therapeutically exploited. For instance, the JAK-STAT pathway is frequently hyperactivated in T-ALL and the use of JAK inhibitors in lymphoid malignancies is currently under pre-clinical investigations. In the present thesis, we took advantage of the TS1 cell line recapitulating in vitro JAK-STAT pathway-driven T-cell transformation in order to unravel the underlying genetic events and evaluate the efficacy of JAK inhibitors. In our first study, we found that growth factor-independent TS1 clones acquired an activating point mutation in JAK1 and/or JAK3, which function as partners in the signal transduction downstream of γc-sharing cytokine receptors. Furthermore, TS1 cells transformed by an activated mutant of JAK1 became resistant to JAK inhibitors by acquiring a secondary mutation in JAK3 and vice versa. We demonstrated that the presence of two inhibitor-sensitive JAK1 and JAK3 mutants cooperatively activate STAT3 and STAT5 factors thereby increasing the resistance to JAK inhibitors. In our second study, we focused on the molecular mechanism underlying the high rate of spontaneous mutagenesis in TS1 cells. We demonstrated that loss of MLH1 expression, a key component of the mismatch repair system, promotes the occurrence of oncogenic point mutations in JAK kinases driving transformation and acquired resistance to inhibitors. We confirmed the clinical relevance of our findings by showing that chronic myeloid leukemia cells from patients that relapsed upon ABL-targeted therapy have a lower expression of MLH1 messenger RNA than leukemic cells from patients at diagnosis. Moreover we identified a particular mutational signature present in our TS1 cell model and corresponding to the one described in primitive CD32+ cells from chronic myeloid leukaemia patients that might attest MLH1-deficiency. Taken together, our findings suggest that MLH1 status should be considered in order to predict response to targeted therapies.

(BIFA - Sciences biomédicales et pharmaceutiques) – UCL, 2015

Advisors/Committee Members: UCL - SSS/DDUV - Institut de Duve, UCL - Faculté de pharmacie et des sciences biomédicales, Renauld, Jean-Christophe, Demoulin, Jean-Baptiste, Knoops, Laurent, De Plaen, Etienne, Van Den Neste, Eric, Graux, Carlos, Haan, Claude, Constantinescu, Stefan.

Subjects/Keywords: JAK; Mismatch repair; MLH1; Mutations; Resistance to TKI

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APA (6^th Edition):

Springuel, L. (2015). Loss of MLH1 expression promotes the acquisition of oncogenic JAK1 and JAK3 mutations that cooperatively increase resistance to JAK inhibitors. (Thesis). Université Catholique de Louvain. Retrieved from http://hdl.handle.net/2078.1/165779

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Springuel, Lorraine. “Loss of MLH1 expression promotes the acquisition of oncogenic JAK1 and JAK3 mutations that cooperatively increase resistance to JAK inhibitors.” 2015. Thesis, Université Catholique de Louvain. Accessed January 18, 2021. http://hdl.handle.net/2078.1/165779.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Springuel, Lorraine. “Loss of MLH1 expression promotes the acquisition of oncogenic JAK1 and JAK3 mutations that cooperatively increase resistance to JAK inhibitors.” 2015. Web. 18 Jan 2021.

Vancouver:

Springuel L. Loss of MLH1 expression promotes the acquisition of oncogenic JAK1 and JAK3 mutations that cooperatively increase resistance to JAK inhibitors. [Internet] [Thesis]. Université Catholique de Louvain; 2015. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2078.1/165779.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Springuel L. Loss of MLH1 expression promotes the acquisition of oncogenic JAK1 and JAK3 mutations that cooperatively increase resistance to JAK inhibitors. [Thesis]. Université Catholique de Louvain; 2015. Available from: http://hdl.handle.net/2078.1/165779

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Dundee

24. Rollings, Christina. The role of JAK1 and JAK3 in CD8⁺ effector T cells.

Degree: PhD, 2016, University of Dundee

URL: https://discovery.dundee.ac.uk/en/studentTheses/03bc71f9-1291-4e6f-9478-11b9b6227f3f ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738560

► The aim of this project was to explore the role of the tyrosine kinases JAK1 and JAK3 in cytokine signalling, focusing on interleukin-2 signalling in… (more)

▼ The aim of this project was to explore the role of the tyrosine kinases JAK1 and JAK3 in cytokine signalling, focusing on interleukin-2 signalling in CD8⁺ effector T lymphocytes. Initial experiments compared the effects of the pan JAK1/JAK3 inhibitor tofacitinib, the selective JAK1 inhibitor GSK186, and the selective JAK3 inhibitor GSK192 on IL-2 control of effector CD8+ cytotoxic T cells (CTL). On the basis of these preliminary data, a detailed analysis of the effect of tofacitinib on effector CD8⁺ T lymphocytes was performed. Phosphorylation events regulated by tofacitinib were identified using mass spectrometry analysis of SILAC (stable isotope labelling with amino acids in cell culture) labelled CTL. Tofacitinib regulated a selective number of phosphorylation sites, with less than 1.2% of the CTL phosphoproteome significantly regulated by tofacitinib treatment following 4hrs tofacitinib treatment. Proteins with downregulated phosphorylation sites were enriched in functions related to the Jak-STAT signalling, regulation of gene expression, and MAPK signalling cascades. Proteins with upregulated phosphorylations were also enriched in functions related to regulation of gene transcription. The proteome of tofacitinib treated CTL was defined by label free mass spectrometry. Approximately 4.5% of the CTL proteome was significantly regulated following 24 hours tofacitinib treatment, suggesting tofacitinib regulates the expression of a selective subset of proteins. Tofacitinib treatment resulted in the downregulation of proteins involved in ribosome biosynthesis, steroid biosynthesis, regulation of transcription and the cell cycle; and the upregulation of proteins with hydrolase activity, and with roles in the lysosome and extracellular exosomes. The phosphoproteomic and proteomic data demonstrates that JAK kinase dependent IL-2 signalling regulates essential processes in CTL by controlling a selective number of phosphorylation events and proteins. Validation of proteins identified as regulated following tofacitinib treatment identified new targets of IL-2 signalling in CTL, including the transcription factor NFIL3. NFIL3 was shown to be upregulated in CD8⁺ T lymphocytes following stimulation with IL-2 and regulated perforin and CD62L expression, suggesting a role in the regulation of CTL effector function.

Subjects/Keywords: IL-2 signalling; CD8 T cells; jak kinases; tofacitinib; NFIL3

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APA (6^th Edition):

Rollings, C. (2016). The role of JAK1 and JAK3 in CD8⁺ effector T cells. (Doctoral Dissertation). University of Dundee. Retrieved from https://discovery.dundee.ac.uk/en/studentTheses/03bc71f9-1291-4e6f-9478-11b9b6227f3f ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738560

Chicago Manual of Style (16^th Edition):

Rollings, Christina. “The role of JAK1 and JAK3 in CD8⁺ effector T cells.” 2016. Doctoral Dissertation, University of Dundee. Accessed January 18, 2021. https://discovery.dundee.ac.uk/en/studentTheses/03bc71f9-1291-4e6f-9478-11b9b6227f3f ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738560.

MLA Handbook (7^th Edition):

Rollings, Christina. “The role of JAK1 and JAK3 in CD8⁺ effector T cells.” 2016. Web. 18 Jan 2021.

Vancouver:

Rollings C. The role of JAK1 and JAK3 in CD8⁺ effector T cells. [Internet] [Doctoral dissertation]. University of Dundee; 2016. [cited 2021 Jan 18]. Available from: https://discovery.dundee.ac.uk/en/studentTheses/03bc71f9-1291-4e6f-9478-11b9b6227f3f ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738560.

Council of Science Editors:

Rollings C. The role of JAK1 and JAK3 in CD8⁺ effector T cells. [Doctoral Dissertation]. University of Dundee; 2016. Available from: https://discovery.dundee.ac.uk/en/studentTheses/03bc71f9-1291-4e6f-9478-11b9b6227f3f ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738560

25. Dolatabadi, Soheila. The role of fusion oncogenes and cancer stem cells in myxoid liposarcoma.

Degree: 2017, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/52409

► Myxoid liposarcoma (MLS) is characterised by the FUS-DDIT3, or the less common EWSR1-DDIT3 fusion oncogene and is the second most common type of liposarcoma. The… (more)

▼ Myxoid liposarcoma (MLS) is characterised by the FUS-DDIT3, or the less common EWSR1-DDIT3 fusion oncogene and is the second most common type of liposarcoma. The fusion oncogenes encode chimeric transcription factors that are causal factors in tumourigenesis however, their functions are poorly known. Notwithstanding continuous progress in treating MLS patients, existing therapies suffer from a major flaw as they do not target the cancer stem cells (CSCs). Unique features of CSCs include self-renewal, tumour initiating capacity and increased resistance to radiotherapy- and chemotherapy-induced cell death. Thus, CSCs are crucial targets for successful therapy. The aims of this project were to define the role of fusion oncogenes in tumourigenesis and to define signalling pathways controlling CSC features in MLS. Here, we demonstrated that MLS has an intact TP53 system that may explain why this tumour entity is genetically stable. We investigated the regulatory mechanisms, expression levels and effects of FUS-DDIT3 in detail, and showed that FUS-DDIT3 was uniquely regulated at both transcriptional and post-translational level. We also screened 70 well-characterised kinase inhibitors and determined their effects on cell proliferation and FUS-DDIT3 expression at mRNA and protein levels. To facilitate these studies, we developed a novel direct lysis approach that enables us to quantify, cell proliferation, mRNA and protein expression in the same sample. This method allowed us to identify a number of previously unknown signalling pathways that regulated the expression of FUS-DDIT3. To study cell division and growth in detail, we applied single-cell analysis on unsynchronized cells at different cell cycle phases and cell sizes. We found that the total transcript level per cell and the expression of most individual genes correlated with progression of the cell cycle, but not with cell size. Detailed studies of cell cycle predictive genes revealed a previously unknown G1 subpopulation. Finally, we showed that MLS contains cells with CSC features and that JAK-STAT signalling controls their numbers. Leukaemia inhibitory factor stimuli increased the number of CSCs, while JAK inhibition depleted the CSC pool. Inhibition of JAK-STAT also showed synergistic effects when combined with chemotherapy in vitro. Our findings concerning FUS-DDIT3 function and CSCs have increased our molecular understanding of tumour development and therapy resistance in MLS that will facilitate development of specific treatment strategies.

Subjects/Keywords: FUS; FUS-DDIT3; myxoid liposarcoma; cancer stem cells; JAK-STAT

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APA (6^th Edition):

Dolatabadi, S. (2017). The role of fusion oncogenes and cancer stem cells in myxoid liposarcoma. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/52409

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Dolatabadi, Soheila. “The role of fusion oncogenes and cancer stem cells in myxoid liposarcoma.” 2017. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed January 18, 2021. http://hdl.handle.net/2077/52409.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Dolatabadi, Soheila. “The role of fusion oncogenes and cancer stem cells in myxoid liposarcoma.” 2017. Web. 18 Jan 2021.

Vancouver:

Dolatabadi S. The role of fusion oncogenes and cancer stem cells in myxoid liposarcoma. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2017. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2077/52409.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Dolatabadi S. The role of fusion oncogenes and cancer stem cells in myxoid liposarcoma. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2017. Available from: http://hdl.handle.net/2077/52409

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Princeton University

26. Wittes, Julia Sarah. A gene expression screen for JAK/STAT and EGFR target genes during Drosophila melanogaster oogenesis .

Degree: PhD, 2018, Princeton University

URL: http://arks.princeton.edu/ark:/88435/dsp01w95053238

► The Janus kinase/Signal transducer and activator of transcription (JAK/STAT) and Epidermal growth factor receptor (EGFR) signaling pathways are conserved regulators of tissue patterning, morphogenesis, and… (more)

▼ The Janus kinase/Signal transducer and activator of transcription (JAK/STAT) and Epidermal growth factor receptor (EGFR) signaling pathways are conserved regulators of tissue patterning, morphogenesis, and other cell biological processes. The Drosophila melanogaster egg chamber is a useful system for studying how signaling regulates epithelial development. During egg chamber development, these signaling pathways are used at multiple points to determine the fates of the epithelial follicle cells. At mid-oogenesis, JAK/STAT and EGFR are both required to specify a population of cells called the posterior follicle cells (PFCs). The PFCs signal to the oocyte to establish the future embryonic axes. In this study, whole genome expression analysis was performed to identify genes activated in egg chambers by JAK/STAT and/or EGFR signaling. 317 genes were identified that are differentially expressed in egg chambers with ectopic JAK/STAT and EGFR pathway activity in the follicle cells. 69 of these candidates were tested for a role in axis establishment using RNAi knockdown in the follicle cells. We were not able to definitively identify any novel posterior signaling genes by this approach. However, we discovered that the signaling protein Sema-1b becomes enriched in the PFCs in response to JAK/STAT and EGFR signaling. Sema-1b RNAi produced a posterior signaling phenotype in our assay; however, an engineered null allele does not appear to cause oocyte polarity defects. We have also identified AdamTS-A as a novel transcriptional target of JAK/STAT signaling in the follicle cells that regulates egg chamber shape. AdamTS-A mRNA becomes enriched at the anterior and posterior poles of the egg chamber at stages 6-7. This mRNA expression pattern appears to be regulated by JAK/STAT signaling. We show that by manipulating AdamTS-A expression it is possible to alter egg chamber shape. AdamTS-A is therefore predicted to function as an effector for JAK/STAT signaling in regulating egg chamber elongation, since it is transcriptionally activated by JAK/STAT signaling and disrupting either JAK/STAT or AdamTS-A interferes with egg chamber elongation. We propose that AdamTS-A regulates egg chamber shape by remodeling the basement membrane at the poles of the egg chamber. Advisors/Committee Members: Schupbach, Trudi M (advisor).

Subjects/Keywords: Drosophila melanogaster; EGFR; JAK/STAT; morphogenesis; oogenesis; patterning

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APA (6^th Edition):

Wittes, J. S. (2018). A gene expression screen for JAK/STAT and EGFR target genes during Drosophila melanogaster oogenesis . (Doctoral Dissertation). Princeton University. Retrieved from http://arks.princeton.edu/ark:/88435/dsp01w95053238

Chicago Manual of Style (16^th Edition):

Wittes, Julia Sarah. “A gene expression screen for JAK/STAT and EGFR target genes during Drosophila melanogaster oogenesis .” 2018. Doctoral Dissertation, Princeton University. Accessed January 18, 2021. http://arks.princeton.edu/ark:/88435/dsp01w95053238.

MLA Handbook (7^th Edition):

Wittes, Julia Sarah. “A gene expression screen for JAK/STAT and EGFR target genes during Drosophila melanogaster oogenesis .” 2018. Web. 18 Jan 2021.

Vancouver:

Wittes JS. A gene expression screen for JAK/STAT and EGFR target genes during Drosophila melanogaster oogenesis . [Internet] [Doctoral dissertation]. Princeton University; 2018. [cited 2021 Jan 18]. Available from: http://arks.princeton.edu/ark:/88435/dsp01w95053238.

Council of Science Editors:

Wittes JS. A gene expression screen for JAK/STAT and EGFR target genes during Drosophila melanogaster oogenesis . [Doctoral Dissertation]. Princeton University; 2018. Available from: http://arks.princeton.edu/ark:/88435/dsp01w95053238

27. Amet, Rebecca. Evaluation of the anti-cancer effects of a novel guanidinium-based compound, VP79s, in multiple myeloma.

Degree: School of Biochemistry & Immunology. Discipline of Biochemistry, 2020, Trinity College Dublin

URL: http://hdl.handle.net/2262/93627

► Multiple myeloma (MM) is an incurable haematological malignancy accounting for 300-350 cancer diagnoses in Ireland each year. Mainly a disease of the elderly, MM is… (more)

▼ Multiple myeloma (MM) is an incurable haematological malignancy accounting for 300-350 cancer diagnoses in Ireland each year. Mainly a disease of the elderly, MM is most prevalent in Western societies where aging populations are rising, and the likelihood of MM is increasing. MM is an extremely arduous malignancy to treat due to the marked clonal heterogeneity among patients. A better understanding of the pathophysiology of MM and advancements in the development of novel therapeutics have allowed the median survival of patients to increase from 3 to 6 years in the past decade. However, despite the effectiveness of the first-line treatments, patients invariably relapse and become refractory to treatment; therefore, novel therapeutics which target this incurable cancer are still required. The Janus kinase (JAK)/Signal transducer and activator of transcription 3 (STAT3) pathway in MM can be both constitutively active due to autonomous mutations or activated by growth and survival factors, such as interleukin-6 (IL-6), secreted by bone marrow stromal cells (BMSCs) and other cells within the bone marrow microenvironment. Increasing evidence has demonstrated that STAT3 is upregulated in MM and that STAT3 increases the expression of genes involved proliferation, angiogenesis and evasion of apoptosis. Consequently, STAT3 has emerged as a therapeutic target in various cancers including MM. In the present study, the anti-MM activity of an optimised series of novel aryl-guanidinium compounds were initially tested in a representative pair of MM cell lines, NCI-H929 and U266B1, and a lead compound, VP79s, was identified. Results with VP79s compared very favourably with those obtained with a panel of standard and emerging therapeutics used to treat MM. In contrast to these therapeutic agents, VP79s equipotently reduced the viability of a panel of myeloma cells with no resistance observed. Following on from this, VP79s was found to induce apoptosis in NCI-H929 and U266B1 cell lines in a dose- and time-dependent manner resulting in caspase 3 activation. The RAS/RAF/MEK/ERK, JAK/STAT, PI3K/AKT and NFĸB signalling pathways are known to play a key role in the pathogenesis of MM. Examination of these pathways found that VP79s rapidly inhibited both constitutively active and IL-6-induced STAT3 signalling in U266B1 and NCI-H929 cells respectively. Examination of upstream mediators of STAT3 signalling suggested that VP79s may inhibit STAT3 via inhibition of JAK2 phosphorylation and downregulation of the IL-6 receptors, CD126 and CD130. Analysis of downstream STAT3 targets demonstrated a decrease in the expression levels of anti-apoptotic Bcl-2 family member, Mcl-1; inhibitor of apoptosis protein, survivin; and the cell cycle protein, cyclin D1. In particular, treatment with VP79s resulted in a rapid time-dependent decrease in Mcl-1, a critical survival factor in MM, suggesting that VP79s may be a promising anti-MM therapeutic. Examination of the translational capacity of VP79s demonstrated that VP79s was able to enhance cell death… Advisors/Committee Members: Zisterer, Daniela.

Subjects/Keywords: Multiple myeloma; Cancer; Drug discovery; JAK/STAT3; Cell signalling

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Amet, R. (2020). Evaluation of the anti-cancer effects of a novel guanidinium-based compound, VP79s, in multiple myeloma. (Thesis). Trinity College Dublin. Retrieved from http://hdl.handle.net/2262/93627

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Amet, Rebecca. “Evaluation of the anti-cancer effects of a novel guanidinium-based compound, VP79s, in multiple myeloma.” 2020. Thesis, Trinity College Dublin. Accessed January 18, 2021. http://hdl.handle.net/2262/93627.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Amet, Rebecca. “Evaluation of the anti-cancer effects of a novel guanidinium-based compound, VP79s, in multiple myeloma.” 2020. Web. 18 Jan 2021.

Vancouver:

Amet R. Evaluation of the anti-cancer effects of a novel guanidinium-based compound, VP79s, in multiple myeloma. [Internet] [Thesis]. Trinity College Dublin; 2020. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2262/93627.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Amet R. Evaluation of the anti-cancer effects of a novel guanidinium-based compound, VP79s, in multiple myeloma. [Thesis]. Trinity College Dublin; 2020. Available from: http://hdl.handle.net/2262/93627

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Melbourne

28. Varghese, Leila Mattea Noozhumurry. Molecular mechanisms of Janus kinase signalling in blood cell development and disease.

Degree: 2014, University of Melbourne

URL: http://hdl.handle.net/11343/41768

► The haematopoietic and immune systems are largely maintained by cytokines, a family of circulating secreted proteins. The binding of cytokines to transmembrane receptors at the… (more)

▼ The haematopoietic and immune systems are largely maintained by cytokines, a family of circulating secreted proteins. The binding of cytokines to transmembrane receptors at the surface of target cells triggers a signalling cascade within the cytoplasm via receptor associated Janus kinases (JAKs), resulting in the transcription of genes that effect a number of biological outcomes, including proliferation, differentiation and survival. A single point mutation resulting in the substitution of a valine for a phenylalanine at residue 617 in JAK2 has been identified as the most common molecular basis of myeloproliferative neoplasms (MPNs). Additional mutations in JAK2 have been subsequently identified in a range of proliferative blood disorders, and are predominantly located in the pseudokinase domain of JAK2, which is known to negatively regulate the kinase activity of this protein. These mutations lead to constitutively activated JAK2, although the mechanisms for this pathological activation are not understood. I expressed and purified a panel of JAK2 tandem kinase and pseudokinase domain constructs incorporating mutations associated with proliferative blood disorders and showed that, in the absence of receptor binding domains, these mutant proteins do not display abnormal catalytic activity and are all inhibited in vitro by SOCS3, a physiological inhibitor of JAKs. Small angle X-ray scattering analyses of these two domains suggest the kinase and pseudokinase domains do not closely interact in cis and support a model where the pseudokinase domain inhibits the kinase domain in trans. Analyses of a JAK2 V617F transgenic mouse model demonstrated that the thrombopoietin receptor, MPL, is essential for thrombocytosis driven by JAK2 V617F. This result was recapitulated in cell lines in which JAK2 V617F expression was inducible, although this was expression level dependent. Lastly, I used insight from disease-causing mutations in MPL and homology modeling to identify residues potentially contributing to ligand binding. In cell-based binding assays using radio-labelled thrombopoietin I was able to identify several residues whose mutation to alanine disrupted ligand binding. In summary, these studies help define the ligand binding domain of the thrombopoietin receptor. Further, these studies support the notion that expression level- and receptor-dependent effects of the JAK2 V617F mutation might contribute to the heterogeneity of disease phenotype, and suggest targeting the receptor interaction and the SOCS3 inhibition site to treat proliferative haematological disorders driven by constitutively activated JAK2.

Subjects/Keywords: JAK-STAT signalling; myeloproliferative neoplasms; thrombopoietin; MPL; SOCS3; JAK2 V617F

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Varghese, L. M. N. (2014). Molecular mechanisms of Janus kinase signalling in blood cell development and disease. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/41768

Chicago Manual of Style (16^th Edition):

Varghese, Leila Mattea Noozhumurry. “Molecular mechanisms of Janus kinase signalling in blood cell development and disease.” 2014. Doctoral Dissertation, University of Melbourne. Accessed January 18, 2021. http://hdl.handle.net/11343/41768.

MLA Handbook (7^th Edition):

Varghese, Leila Mattea Noozhumurry. “Molecular mechanisms of Janus kinase signalling in blood cell development and disease.” 2014. Web. 18 Jan 2021.

Vancouver:

Varghese LMN. Molecular mechanisms of Janus kinase signalling in blood cell development and disease. [Internet] [Doctoral dissertation]. University of Melbourne; 2014. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/11343/41768.

Council of Science Editors:

Varghese LMN. Molecular mechanisms of Janus kinase signalling in blood cell development and disease. [Doctoral Dissertation]. University of Melbourne; 2014. Available from: http://hdl.handle.net/11343/41768

University of Melbourne

29. Scott, Nicholas. Mechanisms and inhibition of CD4+ T cell migration in pre-clinical and humanised mouse models of type 1 diabetes.

Degree: 2017, University of Melbourne

URL: http://hdl.handle.net/11343/194111

► Type 1 diabetes (T1D) is an autoimmune disease that develops when the insulin-secreting beta cells in the pancreas are destroyed. This destruction is primarily mediated… (more)

▼ Type 1 diabetes (T1D) is an autoimmune disease that develops when the insulin-secreting beta cells in the pancreas are destroyed. This destruction is primarily mediated by T cells, of which CD4+ T cells play a central role by controlling immune responses via the production of cytokines. The aim of this thesis was to investigate mechanisms by which CD4+ T cells migrate to the pancreatic islets and kill beta cells, to test a therapeutic method of inhibiting this process, and to develop a mouse model capable of analysing the pathogenicity of human-islet infiltrating CD4+ T cell clones. Deficiency of IFNγ receptor has been reported to prevent the adoptive transfer of CD4+ T cell mediated diabetes. In chapter three, I confirmed these findings and investigate the hypothesis that IFNγ promotes the migration of islet antigen-specific CD4+ T cells by upregulating MHC class II on islet endothelial cells (IEC), thereby providing a cognate antigen signal for diapedesis across the microvessels into the islets. IFNγ treatment of islets led to MHC class II expression on IECs and high MHC class II was detected on IECs in the early stages of insulitis. However, bone marrow chimera experiments revealed MHC class II on IECs is not required for the transfer of CD4+ T cell mediated diabetes. This work rules out antigen presentation by IECs as a putative mechanism for the homing of antigen-specific CD4+ T cells into the pancreatic islets. Cytokines that signal through the JAK-STAT pathway play a role in CD4+ T cell-dependent diabetes. In chapter four, I tested whether JAK1/2 inhibition prevents CD4+ T cell mediated diabetes to determine whether this could be a viable method of blocking cytokine signalling, and pathogenic T-cell responses, in a clinical setting. AZD1480, a JAK1/2 inhibitor, delayed diabetes induced by adoptive transfer of highly diabetogenic CD4+ BDC2.5 T cells. AZD1480 slowed the development of insulitis, and decreased the absolute numbers of leukocytes, including CD4+ T cells, in the islets and pancreatic lymph nodes (PLN), especially reflected in reduced effector-memory T cells. Combined with the recent success of our laboratory in using JAK1/2 inhibitors to abrogate CD8+ T cell mediated diabetes and induce disease reversal, we envision that JAK inhibitors could be trialled in patients at risk of developing type 1 diabetes. Autoimmunity to proinsulin is crucial in the development of diabetes in mice. However, it is unclear whether T cell responses to proinsulin are required for type 1 diabetes in humans. In chapter five, I surveyed the characteristics required to accurately model, in a humanised mouse, CD4+ T-cell responses to proinsulin seen in the pancreatic islets of a deceased organ donor who suffered from T1D. Three components were determined to be necessary: human proinsulin, HLA-DQ8 and chimeric T-cell receptors containing the human TCR variable regions that encode for proinsulin recognition. This led to the generation of a human proinsulin knockin mouse, NOD.HuPI. In this mouse, the murine Ins1 gene…

Subjects/Keywords: Type 1 diabetes; autoimmunity; NOD; JAK inhibitors; humanised mice

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Scott, N. (2017). Mechanisms and inhibition of CD4+ T cell migration in pre-clinical and humanised mouse models of type 1 diabetes. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/194111

Chicago Manual of Style (16^th Edition):

Scott, Nicholas. “Mechanisms and inhibition of CD4+ T cell migration in pre-clinical and humanised mouse models of type 1 diabetes.” 2017. Doctoral Dissertation, University of Melbourne. Accessed January 18, 2021. http://hdl.handle.net/11343/194111.

MLA Handbook (7^th Edition):

Scott, Nicholas. “Mechanisms and inhibition of CD4+ T cell migration in pre-clinical and humanised mouse models of type 1 diabetes.” 2017. Web. 18 Jan 2021.

Vancouver:

Scott N. Mechanisms and inhibition of CD4+ T cell migration in pre-clinical and humanised mouse models of type 1 diabetes. [Internet] [Doctoral dissertation]. University of Melbourne; 2017. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/11343/194111.

Council of Science Editors:

Scott N. Mechanisms and inhibition of CD4+ T cell migration in pre-clinical and humanised mouse models of type 1 diabetes. [Doctoral Dissertation]. University of Melbourne; 2017. Available from: http://hdl.handle.net/11343/194111

University of Melbourne

30. Liau, Nicholas. Structural and biochemical characterisation of the regulation of Janus Kinase signalling.

Degree: 2017, University of Melbourne

URL: http://hdl.handle.net/11343/197686

► The cytokines are a group of extracellular signalling proteins which stimulate a large variety of cellular processes, including the proliferation and differentiation of blood cells,… (more)

▼ The cytokines are a group of extracellular signalling proteins which stimulate a large variety of cellular processes, including the proliferation and differentiation of blood cells, and the up-regulation of the immune system in response to infections. Cytokines are able to bring about such changes by binding to the extracellular domains of specific cytokine receptors displayed on the target cell surface. Cytokine stimulation causes a conformational change to the receptor, activating the Janus Kinases (JAKs), which are attached to the intracellular portion of the receptor. The JAKs are tyrosine kinases, and are able to propagate a signal by phosphorylating downstream substrate proteins, including the Signal Transducers and Activators of Transcription (STATs). Once phosphorylated, the STATs enter the nucleus where they can cause the upregulation of particular gene sets. Whilst cytokine signalling is important for normal cellular function, overactive signalling can be detrimental. Mutations to the JAKs causing overactive signalling have been associated with a group of diseases known as the myeloproliferative neoplasms (MPNs), as well as some cancers. The cell has developed mechanisms to ensure JAK signalling is only active when required. The JAKs are switched off under resting conditions, and only become activated in response to cytokine signalling except for some constitutively active JAK disease-causing mutants. Other proteins are also able to downregulate the JAKs, including the Suppressors of Cytokine Signalling (SOCS) proteins, which are themselves upregulated in response to cytokine signalling to ensure that JAK activation is only transient. In this thesis, SOCS1 was shown to potently downregulate JAK catalytic activity. Structural experiments showed that the short Kinase Inhibitory Region (KIR) of SOCS1 is able to directly inhibit JAK kinase activity by blocking access of substrates to the JAK catalytic site. SOCS1 also contains an SH2 domain, and biochemical experiments showed this domain targets a number of specific phosphotyrosine-containing motifs on the intracellular portions of certain cytokine receptors and on JAKs themselves. Few structural or biochemical studies of full-length JAK (flJAK) proteins have been performed owing to the difficulty of obtaining purified, active, recombinant protein. Following an extensive screen of expression, purification and construct optimisation, methods were successfully developed to obtain high yields of pure, active flJAK1 protein. A biochemical characterisation of flJAK1 was undertaken, demonstrating that the full-length protein binds ATP more tightly, and is catalytically less active than the kinase domain alone showing that other domains regulate kinase activity. Finally, structural studies of full-length JAK1 were undertaken. A complex of flJAK1, SOCS3 and a fragment of the gp130 receptor was successfully crystallised, and crystals diffracted to approximately 8Å resolution, though the three-dimensional structure could not be solved. Low-resolution…

Subjects/Keywords: Janus Kinase; JAK; Suppressor of Cytokine Signalling 1; SOCS1; structural biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Liau, N. (2017). Structural and biochemical characterisation of the regulation of Janus Kinase signalling. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/197686

Chicago Manual of Style (16^th Edition):

Liau, Nicholas. “Structural and biochemical characterisation of the regulation of Janus Kinase signalling.” 2017. Doctoral Dissertation, University of Melbourne. Accessed January 18, 2021. http://hdl.handle.net/11343/197686.

MLA Handbook (7^th Edition):

Liau, Nicholas. “Structural and biochemical characterisation of the regulation of Janus Kinase signalling.” 2017. Web. 18 Jan 2021.

Vancouver:

Liau N. Structural and biochemical characterisation of the regulation of Janus Kinase signalling. [Internet] [Doctoral dissertation]. University of Melbourne; 2017. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/11343/197686.

Council of Science Editors:

Liau N. Structural and biochemical characterisation of the regulation of Janus Kinase signalling. [Doctoral Dissertation]. University of Melbourne; 2017. Available from: http://hdl.handle.net/11343/197686

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