+publisher:"Brown University" +contributor:("Reichner, Jonathan")

1. Oakes, Patrick William. The Liquid Crystalline Transition of F-actin and Neutrophil Mechanosensing.

Degree: PhD, Physics, 2009, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:147/

► This dissertation explores two independent projects in biophysics. Part one focuses on the liquid crystalline phase transition of F-actin. The cytoskeletal protein actin can be… (more)

▼ This dissertation explores two independent projects in biophysics. Part one focuses on the liquid crystalline phase transition of F-actin. The cytoskeletal protein actin can be found in both an unordered isotropic state and an aligned nematic state, and plays an important role in cell structure and motility. The phase transition between these states is predicted to be a first order transition, yet previous results have found it to be continuous. We show here that the transition is truly first order under the proper conditions of high concentration and short average filament lengths. Under this regime, the solution spontaneously separates into ordered domains in the shape of tactoidal droplets. We explore the formation and growth mechanisms of the tactoids and find that the system is only metastable. These findings help clarify the phase separation and co-existence of actin, and may be of relevance to its biological functions. Part two examines the interaction of leukocytes with their substrate. We use polyacrylamide gels to explore the role of the mechanical environment in determining neutrophil behavior. We find that neutrophils spread more and migrate slower but more persistently on stiff substrates. Inhibition of phosphatidylinositol 3-kinase (PI3K) removes this ability of the neutrophil to sense the substrate stiffness, suggesting a role for PI3K in the mechanism responsible for neutrophil mechanosensing. Furthermore, we find that neutrophil force generation is strain limited and independent of substrate stiffness within a limited range. The greatest forces are found in the posterior of the cell, suggesting that the neutrophil pushes, rather than pulls itself forward. Finally, we use polarized T lymphocytes observed under total internal reflection fluorescence (TIRF) microscopy to explore the localization of integrins, the molecules responsible for adhesion to the extracellular matrix. Active integrins are found localized in the anterior of the cell during migration. These findings elucidate the many complex interactions between the cell and substrate, which drive leukocyte behavior. Future studies based on these findings may lead to insights concerning the physiological functions of leukocytes, and in particular how these functions are regulated by the mechanical properties of the surrounding tissues. Advisors/Committee Members: Tang, Jay (director), Reichner, Jonathan (reader), Valles, James (reader).

Subjects/Keywords: actin

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APA (6^th Edition):

Oakes, P. W. (2009). The Liquid Crystalline Transition of F-actin and Neutrophil Mechanosensing. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:147/

Chicago Manual of Style (16^th Edition):

Oakes, Patrick William. “The Liquid Crystalline Transition of F-actin and Neutrophil Mechanosensing.” 2009. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:147/.

MLA Handbook (7^th Edition):

Oakes, Patrick William. “The Liquid Crystalline Transition of F-actin and Neutrophil Mechanosensing.” 2009. Web. 25 Mar 2019.

Vancouver:

Oakes PW. The Liquid Crystalline Transition of F-actin and Neutrophil Mechanosensing. [Internet] [Doctoral dissertation]. Brown University; 2009. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:147/.

Council of Science Editors:

Oakes PW. The Liquid Crystalline Transition of F-actin and Neutrophil Mechanosensing. [Doctoral Dissertation]. Brown University; 2009. Available from: https://repository.library.brown.edu/studio/item/bdr:147/

2. Loosley, Alexander J. The Mechanics of Cell Motility and a Unifying Theory for Characterizing Directed Motion.

Degree: PhD, Physics, 2015, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:419363/

► This dissertation is split into two parts with the first focusing on characterizing cell motility, and the second focusing on linking cell motility to cell… (more)

▼ This dissertation is split into two parts with the first focusing on characterizing cell motility, and the second focusing on linking cell motility to cell mechanics. Cellular motility is routinely characterized by parameters such as migration speed, tortuosity, and persistence time. However, measurements of these parameters are not generally reproducible because their numerical values depend on experimental sampling interval and measurement error. In Part 1, we use random walk theory, simulations, and experimental data to address the need for a metric that quantifies the directionality of a migration path in a manner that decouples from technical parameters. We call this novel metric directionality time because it can be interpreted as the minimum observation time required to determine that the migratory motion is directed. Along with measures of migration speed and persistence, we used the directionality time metric to determine the directedness of chemotactic neutrophil migration paths as a function of physiologically relevant substrate stiffnesses and compositions. We find that engagement of the B2-integrin, CR3, is required for the substrate stiffness dependent regulation of neutrophil honing in 2D on fibronectin. In Part 2, we investigate the role of cell mechanics in cell motility. As cells migrate, they exert cytoskeletal driven contractile forces on their environment. Using spring models with stick-slip adhesion, we are able to predict how the mechanical properties and shape of the cell affect its dynamics and traction forces. We then switch the focus back to neutrophils and explore the relationship between neutrophil contractile force, motility, and the biological response modifier B-glucan, a substance that has shown promise as a clinic grade therapeutic. Using live cell imaging and traction force microscopy to measure neutrophil traction forces as a function of substrate stiffness and β-glucan concentration, we report that increasing the concentration of B-glucan leads to diminished traction forces. Our findings indicate that biological response modifiers may act through the modulation of cell mechanics and motility. Further, we report an overall inverse correlation between migration speed and mechanical output that is affected by B-glucan. These data will be useful for modeling cell motility. Advisors/Committee Members: Tang, Jay (Director), Reichner, Jonathan (Reader), Valles, James (Reader), Pelcovits, Robert (Reader).

Subjects/Keywords: cell motility

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APA (6^th Edition):

Loosley, A. J. (2015). The Mechanics of Cell Motility and a Unifying Theory for Characterizing Directed Motion. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419363/

Chicago Manual of Style (16^th Edition):

Loosley, Alexander J. “The Mechanics of Cell Motility and a Unifying Theory for Characterizing Directed Motion.” 2015. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:419363/.

MLA Handbook (7^th Edition):

Loosley, Alexander J. “The Mechanics of Cell Motility and a Unifying Theory for Characterizing Directed Motion.” 2015. Web. 25 Mar 2019.

Vancouver:

Loosley AJ. The Mechanics of Cell Motility and a Unifying Theory for Characterizing Directed Motion. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:419363/.

Council of Science Editors:

Loosley AJ. The Mechanics of Cell Motility and a Unifying Theory for Characterizing Directed Motion. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419363/

3. Riolo, Matthew T. HDAC6 restrict acetylated survivin nuclear export.

Degree: PhD, Pathobiology, 2012, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:297559/

► Survivin is an oncofetal protein expressed in most tumors. It is a unique member of the inhibitor of apoptosis family of proteins having a dual… (more)

▼ Survivin is an oncofetal protein expressed in most tumors. It is a unique member of the inhibitor of apoptosis family of proteins having a dual function dependent on its subcellular localization. Nuclear survivin is a critical member of the chromosomal passenger complex essential for normal cell division, while cytoplasmic survivin is antiapoptotic through indirect inhibition of caspase activation. Critical to regulating survivin's different functions are post-translational modifications such as phosphporylation and ubiquitination, however a role for acetylation has yet to be investigated. In this dissertation ten novel survivin acetylation sites were identified and it was found that one in particular, lysine 129, is an important regulator of survivin subcellular localization. Using transfection assays, the specificity of a novel survivin 129 acetylation antibody was established and used to determine the histone deacetylase responsible for survivin 129 deacetylation. First, treatment of cancer cells with different chemical inhibitors revealed survivin 129 deacetylation occurs by a member of the class I/II HDAC family. Multiple transfection assays identified HDAC6 as a primary deacetylase of survivin at lysine 129 and experiments with HDAC6 mutant constructs indicated that domain II is essential for this deacetylase activity. Subcellular fractionation revealed survivin 129 acetylation occurs in the nucleus, while HDAC6 resides in the cytoplasm. However, transfection with CBP increased HDAC6 expression, nuclear localization, and interaction with survivin suggesting a putative role of CBP in regulating HDAC6 function. In ER+ breast cancer cells, treatment with estrogen increased survivin expression, nuclear localization, and 129 acetylation, as well as increased HDAC6 expression and nuclear localization. Together, these results suggest a delicate regulation of survivin 129 acetylation/deacetylation mediated through alterations in growth factor activated pathways. This dissertation identifies HDAC6 as a primary deacetylase of survivin 129 acetylation and indicates a novel mechanism of CBP mediated HDAC6 nuclear localization. Further, results with estrogen treatment suggest survivin 129 acetylation is regulated through a growth factor mediated pathway in ER+ breast cancer cells. Advisors/Committee Members: Altura, Rachel (Director), Reichner, Jonathan (Reader), Chin, Eugene (Reader), Marshall, John (Reader), Fumihiko, Urano (Reader).

Subjects/Keywords: HDAC6

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APA (6^th Edition):

Riolo, M. T. (2012). HDAC6 restrict acetylated survivin nuclear export. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297559/

Chicago Manual of Style (16^th Edition):

Riolo, Matthew T. “HDAC6 restrict acetylated survivin nuclear export.” 2012. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:297559/.

MLA Handbook (7^th Edition):

Riolo, Matthew T. “HDAC6 restrict acetylated survivin nuclear export.” 2012. Web. 25 Mar 2019.

Vancouver:

Riolo MT. HDAC6 restrict acetylated survivin nuclear export. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:297559/.

Council of Science Editors:

Riolo MT. HDAC6 restrict acetylated survivin nuclear export. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297559/

4. Heflin, Katie Elizabeth. The effects of extracellular matrix proteins and fungal �glucan on CR3 structure, neutrophil migration and mechanosensing.

Degree: PhD, Pathobiology, 2011, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:11296/

► Neutrophils are the body�s first cellular line of defense. Many of their functions are regulated by integrins through interactions with extracellular matrix (ECM). Insufficient activity… (more)

▼ Neutrophils are the body�s first cellular line of defense. Many of their functions are regulated by integrins through interactions with extracellular matrix (ECM). Insufficient activity of integrins results in infections and impaired healing, while excessive activity leads to inflammation and tissue damage. The � integrin CR3 has a unique lectin-like domain which binds carbohydrates, including the fungal pathogen associated molecular pattern �glucan. CR3 binding of ECM, carbohydrate or both differentially regulates neutrophil function, though the mechanism is not clearly understood.Using functional proteomic techniques, a set of phosphopeptides that are regulated in a CR3-dependent manner by �glucan were identified, confirming CR3 as a signaling receptor for �glucan. Intracellular and extracellular changes in CR3 structure were assessed using fluorescence resonance energy transfer reporters. While the ECM ligand fibrinogen (Fgn) alone induced full activation of CR3 (headpiece extension and cytoplasmic tail separation), �glucan alone or with Fgn stabilized an intermediate conformation with moderate headpiece extension and full cytoplasmic tail separation.Neutrophils migrate through microenvironments with a range of mechanical properties, which can be altered in disease. The migration dynamics (relative rate and directionality) of neutrophils on surfaces of varying ECM protein composition and stiffness were quantified and compared. The mechanosensitivity of neutrophil migration is substrate-dependent, with stiffness-dependent migration dynamics varying in response to individual ECM proteins and mixtures. Inhibitor studies suggest that the PI-3-kinase pathway is involved in regulating migration dynamics under these conditions. Although migration on Fgn was unaffected by surface stiffness, neutrophils treated with �glucan showed mechanosensitive differences in their migration rate.This dissertation explored the effects of �glucan on CR3 structure and signaling and represents the first direct evidence of soluble �glucan binding and affecting receptors on living cells. These studies have also investigated the effects of �glucan on neutrophil migration and mechanosensing across a variety of ECM proteins. Advisors/Committee Members: Reichner, Jonathan (Director), Hixson, Douglas (Reader), Salazar-Mather, Thais (Reader), Tang, Jay (Reader), Hammer, Daniel (Reader).

Subjects/Keywords: CR3

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APA (6^th Edition):

Heflin, K. E. (2011). The effects of extracellular matrix proteins and fungal �glucan on CR3 structure, neutrophil migration and mechanosensing. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:11296/

Chicago Manual of Style (16^th Edition):

Heflin, Katie Elizabeth. “The effects of extracellular matrix proteins and fungal �glucan on CR3 structure, neutrophil migration and mechanosensing.” 2011. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:11296/.

MLA Handbook (7^th Edition):

Heflin, Katie Elizabeth. “The effects of extracellular matrix proteins and fungal �glucan on CR3 structure, neutrophil migration and mechanosensing.” 2011. Web. 25 Mar 2019.

Vancouver:

Heflin KE. The effects of extracellular matrix proteins and fungal �glucan on CR3 structure, neutrophil migration and mechanosensing. [Internet] [Doctoral dissertation]. Brown University; 2011. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:11296/.

Council of Science Editors:

Heflin KE. The effects of extracellular matrix proteins and fungal �glucan on CR3 structure, neutrophil migration and mechanosensing. [Doctoral Dissertation]. Brown University; 2011. Available from: https://repository.library.brown.edu/studio/item/bdr:11296/

5. Chung, Waihong. MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS TRANSGENIC MICE.

Degree: PhD, Pathobiology, 2015, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:419352/

► Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer death in the United States. Chronic… (more)

Subjects/Keywords: Hepatocellular

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APA (6^th Edition):

Chung, W. (2015). MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS TRANSGENIC MICE. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419352/

Chicago Manual of Style (16^th Edition):

Chung, Waihong. “MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS TRANSGENIC MICE.” 2015. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:419352/.

MLA Handbook (7^th Edition):

Chung, Waihong. “MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS TRANSGENIC MICE.” 2015. Web. 25 Mar 2019.

Vancouver:

Chung W. MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS TRANSGENIC MICE. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:419352/.

Council of Science Editors:

Chung W. MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS IN ATX/IRS TRANSGENIC MICE. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419352/

6. Magruder, Hilary. Signaling Effectors Required for G Protein-Coupled Estrogen Receptor-, GPER, Induced Events Associated with Breast Cancer Progression.

Degree: PhD, Pathobiology, 2014, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:386260/

► Stimulation of estrogen receptor (ER)-negative human breast cancer cells with 17β-estradiol (E2β) results in fibronectin (FN) matrix assembly and transactivation of the epidermal growth factor… (more)

▼ Stimulation of estrogen receptor (ER)-negative human breast cancer cells with 17β-estradiol (E2β) results in fibronectin (FN) matrix assembly and transactivation of the epidermal growth factor receptor (EGFR) via the G protein-coupled estrogen receptor (GPER). This mechanism of action results in the recruitment of FN-engaged integrin α5β1 to fibrillar adhesions and the formation of integrin α5β1-Shc adaptor protein complexes. Here, we show that GPER stimulation of murine 4T1 or human SKBR3 breast cancer cells promotes the formation of focal adhesions, actin stress fibers, and results in increased cellular adhesion and haptotaxis on FN, but not collagen. These actions are also induced by the xenoestrogen, bisphenol A, and the ER antagonist, ICI 182, 780, but not the inactive stereoisomer, 17α-estradiol (E2α). In addition, we show that GPER stimulation of breast cancer cells allows for FN-dependent, anchorage-independent growth and FN fibril formation in hanging drop assays, indicating that these GPER-mediated actions occur independently of adhesion to solid substrata. Furthermore, stable expression of Shc mutant Y317F lacking its primary tyrosyl phosphorylation site disrupts E2β-induced focal adhesion and actin stress fiber formation, and abolishes E2β-enhanced haptotaxis on FN and anchorage-dependent growth. We also show that overexpression of a phosphatase, PTPN12, known to interact with Shc inhibits focal adhesion and FN fibril formation, adhesion and haptotaxis on FN, and anchorage independent growth. Moreover, PTPN12 knockdown positively influences these events associated with cellular survival. Collectively, these data demonstrate that E2β action via GPER enhances cellular adhesivity and FN matrix assembly and allows for anchorage-independent growth, cellular events that may allow for cellular survival and tumor progression. Advisors/Committee Members: Filardo, Edward (Director), Reichner, Jonathan (Reader), Freiman, Richard (Reader), Yang, Wentian (Reader), Prossnitz, Eric (Reader).

Subjects/Keywords: estrogen receptor (ER)

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APA (6^th Edition):

Magruder, H. (2014). Signaling Effectors Required for G Protein-Coupled Estrogen Receptor-, GPER, Induced Events Associated with Breast Cancer Progression. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386260/

Chicago Manual of Style (16^th Edition):

Magruder, Hilary. “Signaling Effectors Required for G Protein-Coupled Estrogen Receptor-, GPER, Induced Events Associated with Breast Cancer Progression.” 2014. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:386260/.

MLA Handbook (7^th Edition):

Magruder, Hilary. “Signaling Effectors Required for G Protein-Coupled Estrogen Receptor-, GPER, Induced Events Associated with Breast Cancer Progression.” 2014. Web. 25 Mar 2019.

Vancouver:

Magruder H. Signaling Effectors Required for G Protein-Coupled Estrogen Receptor-, GPER, Induced Events Associated with Breast Cancer Progression. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:386260/.

Council of Science Editors:

Magruder H. Signaling Effectors Required for G Protein-Coupled Estrogen Receptor-, GPER, Induced Events Associated with Breast Cancer Progression. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386260/

7. Biron, Bethany. The Role of Peptidyl arginine deiminase, type IV (PAD4) in the Pathology of Shock/Sepsis.

Degree: Pathobiology, 2017, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:733274/

► Sepsis is a life threatening condition that elicits a dysregulated and damaging immune response, which in turn leads to tissue damage and Multiple Organ Dysfunction… (more)

▼ Sepsis is a life threatening condition that elicits a dysregulated and damaging immune response, which in turn leads to tissue damage and Multiple Organ Dysfunction (MOD). Critically ill patients that have suffered from trauma, complex surgery, gastrointestinal bleeding, obstetrical bleeding, etc., have an increased risk of developing sepsis, which may progress to Acute Respiratory Distress Syndrome (ARDS), leading in turn to an increase in mortality. Neutrophils are thought to play a role in the immune dysfunction seen in both shock and sepsis, and have been implicated in causing bystander tissue damage and organ dysfunction. Neutrophil extracellular traps (NETs) are large webs of decondensed chromatin coated with antimicrobial proteins that are released into the extracellular space. They serve as a novel effector function, regulated by the enzyme Peptidyl arginine deiminase, type IV (PAD4). NETs have been identified as an important aspect of innate immunity, but have also been linked to excessive inflammation and tissue damage. Their role in sepsis and shock/sepsis, however, is poorly understood. This dissertation examines how PAD4 (an enzyme central to NET formation) plays a role in the pathology of sepsis. It also examines whether a predispositional insult, such as severe shock antecedent to septic challenge, is affected this enzyme. Here we demonstrate that inhibition of PAD4 reduces mortality seen in a mouse polymicrobial sepsis model (CLP), as well as in a mouse model of hemorrhagic shock and sepsis (Hem/CLP). Clinically we showed that there is evidence of increased NET activity in septic patients. Together, this implies that PAD4-mediated NET formation contributes to the morbidity and mortality associated with sepsis and shock/sepsis, and that PAD4 merits further exploration as a possible therapeutic target against the damaging pro-inflammatory response seen in polymicrobial sepsis and indirect ARDS. Advisors/Committee Members: Ayala, Alfred (Advisor), Reichner, Jonathan (Reader), Lefort, Craig (Reader), Heffernan, Daithi (Reader), Levy, Bruce (Reader).

Subjects/Keywords: Cellular immunity

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APA (6^th Edition):

Biron, B. (2017). The Role of Peptidyl arginine deiminase, type IV (PAD4) in the Pathology of Shock/Sepsis. (Thesis). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:733274/

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):

Biron, Bethany. “The Role of Peptidyl arginine deiminase, type IV (PAD4) in the Pathology of Shock/Sepsis.” 2017. Thesis, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:733274/.

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

MLA Handbook (7^th Edition):

Biron, Bethany. “The Role of Peptidyl arginine deiminase, type IV (PAD4) in the Pathology of Shock/Sepsis.” 2017. Web. 25 Mar 2019.

Vancouver:

Biron B. The Role of Peptidyl arginine deiminase, type IV (PAD4) in the Pathology of Shock/Sepsis. [Internet] [Thesis]. Brown University; 2017. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:733274/.

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

Council of Science Editors:

Biron B. The Role of Peptidyl arginine deiminase, type IV (PAD4) in the Pathology of Shock/Sepsis. [Thesis]. Brown University; 2017. Available from: https://repository.library.brown.edu/studio/item/bdr:733274/

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

8. Cao, Cong. The role of inhibitory heterotrimeric G proteins in Receptor Tyrosine Kinase function and identification of defective TrkB signaling in Angelman Syndrome.

Degree: PhD, Pathobiology, 2011, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:11272/

► The Epidermal growth factor (EGF) receptor (EGFR), tropomyosin-receptor kinase (Trk) and other receptor tyrosine kinase (RTK) family members play pivotal roles in regulating the normal… (more)

▼ The Epidermal growth factor (EGF) receptor (EGFR), tropomyosin-receptor kinase (Trk) and other receptor tyrosine kinase (RTK) family members play pivotal roles in regulating the normal biological process and malignant transformation. They activate downstream transduction signal transduction cascades, that include the phosphoinositide 3-kinase (PI3K) /AKT/ mammalian target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase (MAPK) pathways, which are vital for cell proliferation, growth, migration and survival. However, it is still not entirely understood how the RTK transduces signals to PI3K/AKT/ mTORC1 and MAPK. The first part of this thesis focuses on the role of heterotrimeric G protein alpha subunits, Gai1 and Gai3, in this process. We identify an association of Gai proteins with the RTK and the adaptor protein Gab1 (Grb2 associated bind 1). This interaction is required for subsequent Gab1 phosphorylation, and downstream activation of the AKT-mTOR and the MAPK pathways in response to RTK ligands, including EGF and brain-derived neurotrophic factor (BDNF). This study demonstrates a novel role between Gai proteins, traditionally known as components in G-protein coupled receptor (GPCR) signaling, and RTK signaling. Angelman Syndrome (AS) is a neurological disorder caused by a loss of maternal expression of the ubiquitin E3 ligase gene UBE3A. Common symptoms of AS include developmental delay, mental retardation, excessive inappropriate laughter, movement ataxia, seizures, and lack of speech. The precise molecular mechanisms which cause the symptoms of Angelman Syndrome, however, are still not completely understood. We discovered that BDNF/TrkB signaling is deficient in Angelman Syndrome (AS) mice, providing a possible explanation for LTP (long-term potentiation) loss and other symptoms associated with Angelman Syndrome. CN 2097, a newly synthesized cyclic peptide designed to target the PDZ domains of the PSD-95, rescued BDNF signaling and LTP in AS mice. PSD-95 forms a complex with TrkB after BDNF treatment and CN 2097 increased this association to enhance PI3K/AKT and CaMKII signaling. This study suggests that CN 2097 may represent a new therapeutic option for treating this disease. Advisors/Committee Members: Marshall, John (Director), Bowen, Wayne (Reader), Green, William (Reader), Biron, Christine (Reader), Reichner, Jonathan (Reader).

Subjects/Keywords: receptor tyrosine kinase signaling

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APA (6^th Edition):

Cao, C. (2011). The role of inhibitory heterotrimeric G proteins in Receptor Tyrosine Kinase function and identification of defective TrkB signaling in Angelman Syndrome. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:11272/

Chicago Manual of Style (16^th Edition):

Cao, Cong. “The role of inhibitory heterotrimeric G proteins in Receptor Tyrosine Kinase function and identification of defective TrkB signaling in Angelman Syndrome.” 2011. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:11272/.

MLA Handbook (7^th Edition):

Cao, Cong. “The role of inhibitory heterotrimeric G proteins in Receptor Tyrosine Kinase function and identification of defective TrkB signaling in Angelman Syndrome.” 2011. Web. 25 Mar 2019.

Vancouver:

Cao C. The role of inhibitory heterotrimeric G proteins in Receptor Tyrosine Kinase function and identification of defective TrkB signaling in Angelman Syndrome. [Internet] [Doctoral dissertation]. Brown University; 2011. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:11272/.

Council of Science Editors:

Cao C. The role of inhibitory heterotrimeric G proteins in Receptor Tyrosine Kinase function and identification of defective TrkB signaling in Angelman Syndrome. [Doctoral Dissertation]. Brown University; 2011. Available from: https://repository.library.brown.edu/studio/item/bdr:11272/

9. Linden, Jennifer R. Galectin-3 and Candidiasis: Its Role in Human Neutrophil Phagocytosis and in Disseminated Disease.

Degree: PhD, Pathobiology, 2012, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:297569/

► Candida albicans causes the majority of invasive candidiasis in immunocompromised adults while Candida parapsilosis is a leading cause of neonatal candidiasis. While considerable study has… (more)

▼ Candida albicans causes the majority of invasive candidiasis in immunocompromised adults while Candida parapsilosis is a leading cause of neonatal candidiasis. While considerable study has focused on how the immune system recognizes and responds to C. albicans, little is known about host interactions with C. parapsilosis. This study investigated the human neutrophil response to these two species. Human neutrophils phagocytosed C. parapsilosis much more efficiently than C. albicans yeast and exhibited distinctly different morphological responses. Subsequent experiments focused on the identification of the fungal ligand and neutrophil receptors involved in efficient phagocytosis of C. parapsilosis. To identify the fungal ligand involved, neutrophils were treated with soluble components of the fungal cell wall including β-glucan, chitin and mannan extracted from C. parapsilosis, C. albicans and S. cerevisiae. Mannan extracted from C. parapsilosis inhibited phagocytosis of whole C. parapsilosis yeast, indicating that C. parapsilosis mannan may be the ligand initiating phagocytosis. To identify the neutrophil receptor involved in efficient phagocytosis, neutrophils were treated with blocking antibodies against dectin-1, TLR2, TLR4, TLR6, CR3 and galectin-3. Only treatment with the galectin-3 blocking antibody inhibited phagocytosis of C. parapsilosis yeast, but not C. albicans yeast. Treatment with the galectin-3 antibody also inhibited efficient phagocytosis of C. albicans hyphae. The majority of neutrophil galectin-3 was expressed intracellularly but was secreted when treated with C. parapsilosis mannan. When neutrophils were treated with exogenous galectin-3, phagocytosis of both C. albicans and C. parapsilosis yeast increased. Exposure of neutrophils to C. parapsilosis increased phagocytosis of C. albicans yeast and was inhibited by galectin-3 blocking antibody. Taken together, these data indicate that galectin-3 secreted from neutrophils may act as a proinflammatory autocrine/paracrine signal in neutrophil phagocytosis. Mice deficient in galectin-3 were more susceptible to infection with either C. parapsilosis or C. albicans. Interestingly, serum galectin-3 levels were lower in human newborns when compared to adults. These data suggest that galectin-3 has a unique role in neutrophil recognition of C. parapsilosis distinct from C. albicans and protects against disseminated candidiasis. Advisors/Committee Members: Bliss, Joseph (Director), Bennett, Richard (Reader), Shaw, Sunil (Reader), Reichner, Jonathan (Reader), Levitz, Stuart (Reader).

Subjects/Keywords: Candida parapsilosis

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APA (6^th Edition):

Linden, J. R. (2012). Galectin-3 and Candidiasis: Its Role in Human Neutrophil Phagocytosis and in Disseminated Disease. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297569/

Chicago Manual of Style (16^th Edition):

Linden, Jennifer R. “Galectin-3 and Candidiasis: Its Role in Human Neutrophil Phagocytosis and in Disseminated Disease.” 2012. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:297569/.

MLA Handbook (7^th Edition):

Linden, Jennifer R. “Galectin-3 and Candidiasis: Its Role in Human Neutrophil Phagocytosis and in Disseminated Disease.” 2012. Web. 25 Mar 2019.

Vancouver:

Linden JR. Galectin-3 and Candidiasis: Its Role in Human Neutrophil Phagocytosis and in Disseminated Disease. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:297569/.

Council of Science Editors:

Linden JR. Galectin-3 and Candidiasis: Its Role in Human Neutrophil Phagocytosis and in Disseminated Disease. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297569/

10. Toyjanova, Jennet. The Effect of Confinement on Neutrophil Force Generation.

Degree: PhD, Mechanics of Solids, 2015, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:419365/

► Generation of forces is essential for the migration of neutrophils to the sites of infection or injury. The mechanical properties and local confinement of the… (more)

Subjects/Keywords: cell mechanics

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APA (6^th Edition):

Toyjanova, J. (2015). The Effect of Confinement on Neutrophil Force Generation. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419365/

Chicago Manual of Style (16^th Edition):

Toyjanova, Jennet. “The Effect of Confinement on Neutrophil Force Generation.” 2015. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:419365/.

MLA Handbook (7^th Edition):

Toyjanova, Jennet. “The Effect of Confinement on Neutrophil Force Generation.” 2015. Web. 25 Mar 2019.

Vancouver:

Toyjanova J. The Effect of Confinement on Neutrophil Force Generation. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:419365/.

Council of Science Editors:

Toyjanova J. The Effect of Confinement on Neutrophil Force Generation. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419365/

11. Newsome, Courtni Takiyah. Effects of Beta-Glucan on Sepsis and Endotoxemia.

Degree: PhD, Pathobiology, 2010, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:11086/

► Beta-glucans are glucose polymers found of the fungal cell wall. Beta-glucans have immunological effects and can stimulate innate immune cells. Priming immune cell function can… (more)

▼ Beta-glucans are glucose polymers found of the fungal cell wall. Beta-glucans have immunological effects and can stimulate innate immune cells. Priming immune cell function can be of clinical benefit, however, it results in the overproduction of pro-inflammatory cytokines which may be detrimental to the patient. The soluble, beta-glucan PGG-glucan, which was prepared from Saccharomyces cerevisiae, primes antimicrobial functions without stimulating cytokines. The prophylactic effects of beta-glucan have been evaluated, however, it is unknown if PGG-beta-glucan can be beneficial when given to a patient or an experimental animal that is already infected. Our first aim was to evaluate the effect of PGG-glucan on the mortality of and cytokine production and bacteremia in septic mice induced by cecal ligation and puncture (CLP) when administered after the onset of infection. These results indicate that PGG-glucan given 1 hour after CLP enhanced 10-day survival in female mice but not in male mice. Elevated IL-6 levels predicted mortality, however, differences in IL-6 values determined to predict 100% mortality between the sexes existed. PGG-glucan did not increase 10-day survival in ovariectomized female mice or in ovariectomized female mice given a dose of estrogen, indicating that hormones play a role in protection mediated by PGG-glucan, and that estrogen is necessary, but not sufficient for protection. PGG-glucan reduced IL-6 and IL-10 levels in male and female mice. Next, we evaluated the effect of PGG-glucan pretreatment on the LPS-induced TNF production in vivo. The results indicate that PGG-glucan pretreatment for 96 hours prior to LPS stimulation reduced TNF, IL-6 and IL-10 production in 4-5 month old male mice, but not in 6-8 week old male mice. The results also indicate that PGG-glucan attenuated TNF production in 20 month old female mice, but not in 6-8 week old or 4-5 month old female mice. PGG-glucan could be developed as a therapeutic agent to potentiate immune cell functions of patients without inducing the negative side effects of cytokine production. Advisors/Committee Members: Reichner, Jonathan (Director), Ayala, Alfred (Reader), Moss, Steven (Reader), Sharma, Surendra (Reader), Sherwood, Edrward (Reader).

Subjects/Keywords: beta-glucan

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APA (6^th Edition):

Newsome, C. T. (2010). Effects of Beta-Glucan on Sepsis and Endotoxemia. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:11086/

Chicago Manual of Style (16^th Edition):

Newsome, Courtni Takiyah. “Effects of Beta-Glucan on Sepsis and Endotoxemia.” 2010. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:11086/.

MLA Handbook (7^th Edition):

Newsome, Courtni Takiyah. “Effects of Beta-Glucan on Sepsis and Endotoxemia.” 2010. Web. 25 Mar 2019.

Vancouver:

Newsome CT. Effects of Beta-Glucan on Sepsis and Endotoxemia. [Internet] [Doctoral dissertation]. Brown University; 2010. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:11086/.

Council of Science Editors:

Newsome CT. Effects of Beta-Glucan on Sepsis and Endotoxemia. [Doctoral Dissertation]. Brown University; 2010. Available from: https://repository.library.brown.edu/studio/item/bdr:11086/

12. Nevers, Tania A. Inflammatory and dysfunctional regulatory T cells in adverse pregnancy outcomes.

Degree: PhD, Pathobiology, 2012, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:297562/

► The etiologies for adverse pregnancy outcomes such as recurrent spontaneous abortion, preeclampsia, preterm birth and gestational diabetes mellitus (GDM) are multi-factorial and remain poorly understood.… (more)

▼ The etiologies for adverse pregnancy outcomes such as recurrent spontaneous abortion, preeclampsia, preterm birth and gestational diabetes mellitus (GDM) are multi-factorial and remain poorly understood. The main reasons for enigmatic state of adverse pregnancy outcomes can be assigned to lack of well defined animal models in response to inflammatory triggers and early pregnancy predictive assays and biomarkers. However, these pregnancy complications have a common contributor in inflammation at the maternal-fetal interface. In normal pregnancy, a state of immune tolerance is choreographed involving pro- and anti-inflammatory signals. Regulatory T cells (Tregs) have acquired a premier role in regulating immune tolerance systemically and at the maternal-fetal interface. Here we focus on Tregs for their phenotypic and functional dysregulation in mouse and human models of pregnancy complications. Importantly, we invoke the role of IL-10, a signature cytokine of Tregs, and human chorionic gonadotropin (hCG) in maintaining normal pregnancy. Our overarching hypothesis is that uterine regulatory T cells are dysfunctional in adverse pregnancies associated with infection and /or inflammation and may be normalized by IL-10 and hCG. This work explores dysregulation of uterine Tregs by utilizing mouse models of adverse pregnancies, human peripheral blood Tregs and sera from normal pregnancy, preeclampsia and gestational diabetes. In Chapter 2, we show that uterine regulatory T cells amplify and acquire an inflammatory phenotype in response to the TLR-3 agonist and cause pregnancy demise in IL-10-/- and wild-type (WT) mice. In Chapter 3, we present for the first time that peripheral blood Tregs from GDM patients present an “exhausted” phenotype and express the programmed death receptor (PD-1). Tregs from GDM lose CD25 and Foxp3 expression upon overnight culturing which can be partially rescued by TGF-β, IL-2, or PD-1 blockade. This phenotype was not observed in Tregs from normal pregnancy. In Chapter 4, we describe that hCG produced in preeclampsia is inactive and does not support angiogenesis and recruitment of Tregs to the uterus in the “humanized” mouse model of preeclampsia. Collectively, the results presented in this thesis provide novel pathways by which regulatory T cells can present themselves as foes of normal pregnancy. Advisors/Committee Members: Sharma, Surendra (Director), Ayala, alfred (Reader), Fast, Loren (Reader), Reichner, Jonathan (Reader), Golos, Thaddeus (Reader).

Subjects/Keywords: Regulatory T cells

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APA (6^th Edition):

Nevers, T. A. (2012). Inflammatory and dysfunctional regulatory T cells in adverse pregnancy outcomes. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297562/

Chicago Manual of Style (16^th Edition):

Nevers, Tania A. “Inflammatory and dysfunctional regulatory T cells in adverse pregnancy outcomes.” 2012. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:297562/.

MLA Handbook (7^th Edition):

Nevers, Tania A. “Inflammatory and dysfunctional regulatory T cells in adverse pregnancy outcomes.” 2012. Web. 25 Mar 2019.

Vancouver:

Nevers TA. Inflammatory and dysfunctional regulatory T cells in adverse pregnancy outcomes. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:297562/.

Council of Science Editors:

Nevers TA. Inflammatory and dysfunctional regulatory T cells in adverse pregnancy outcomes. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297562/

13. Valm, Alex Mihkel. Combinatorial Labeling and Spectral Imaging (CLASI): A novel microscopy method for the systems-level analysis of biological structure and its application to the study of human oral microbial community organization.

Degree: PhD, Pathobiology, 2012, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:297560/

► Just as the phenotypically different cells that make up multicellular organisms are distributed in tissues with structures that embody specific functions, microbial cells with different… (more)

▼ Just as the phenotypically different cells that make up multicellular organisms are distributed in tissues with structures that embody specific functions, microbial cells with different metabolic functions form unique spatial structures and coordinate their activities as multicellular units, e.g. biofilms. Fundamentally, microbial communities differ from eukaryotic tissues because their cellular constituents may be genetically distinct; in fact, up to hundreds of different species may be present in a single biofilm. Any number of probes may be designed to identify the different species present in a community; however, the ability to unambiguously distinguish more than a few different labels in a single fluorescence image has been severely hampered by the excitation cross talk and signal bleed-through of fluorophores with highly overlapping emission spectra. Reported in this thesis is a fluorescence labeling, imaging, and analysis method to greatly expand the number of identifiable labels in a single image, which we call Combinatorial Labeling and Spectral Imaging (CLASI). Application of our CLASI technique to human dental plaque using fluorescence in situ hybridization (FISH) enabled the first quantitative analysis of the spatial distribution of 15 different taxa of microbes in a biofilm. Proximity analysis was used to determine the frequency of inter- and intrataxon cell-to-cell associations, which revealed statistically significant intertaxon pairings. Cells of the genera Prevotella and Actinomyces showed the most interspecies associations, suggesting a central role for these genera in establishing and maintaining biofilm complexity. In a proof-of-principle experiment, we further demonstrate that we can distinguish 120 differently labeled E. coli in a mixture labeled with binary combinations of 16 fluorophores using a novel linear unmixing algorithm constrained to identify specific combinations of fluorophores. Our results provide an initial systems-level structural analysis of biofilm organization and we further believe that the CLASI approach will be useful for the architectural analysis of many complex molecular structures within cells. Advisors/Committee Members: Oldenbourg, Rudolf (Director), Borisy, Gary (Director), Atwood, Walter (Reader), Reichner, Jonathan (Reader), Danuser, Gaudenz (Reader).

Subjects/Keywords: fluorescence imaging

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APA (6^th Edition):

Valm, A. M. (2012). Combinatorial Labeling and Spectral Imaging (CLASI): A novel microscopy method for the systems-level analysis of biological structure and its application to the study of human oral microbial community organization. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297560/

Chicago Manual of Style (16^th Edition):

Valm, Alex Mihkel. “Combinatorial Labeling and Spectral Imaging (CLASI): A novel microscopy method for the systems-level analysis of biological structure and its application to the study of human oral microbial community organization.” 2012. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:297560/.

MLA Handbook (7^th Edition):

Valm, Alex Mihkel. “Combinatorial Labeling and Spectral Imaging (CLASI): A novel microscopy method for the systems-level analysis of biological structure and its application to the study of human oral microbial community organization.” 2012. Web. 25 Mar 2019.

Vancouver:

Valm AM. Combinatorial Labeling and Spectral Imaging (CLASI): A novel microscopy method for the systems-level analysis of biological structure and its application to the study of human oral microbial community organization. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:297560/.

Council of Science Editors:

Valm AM. Combinatorial Labeling and Spectral Imaging (CLASI): A novel microscopy method for the systems-level analysis of biological structure and its application to the study of human oral microbial community organization. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297560/

14. Jiz, Mario Antonio II L. Vaccine Development in Schistosomiasis japonica: Paramyosin As a Leading Candidate.

Degree: PhD, Division of Biology and Medicine. Pathobiology, 2009, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:175/

► Schistosomiasis is a chronic debilitating disease caused by helminths of the genus Schistosoma, and currently affecting millions in the developing world. Treatment with Praziquantel has… (more)

▼ Schistosomiasis is a chronic debilitating disease caused by helminths of the genus Schistosoma, and currently affecting millions in the developing world. Treatment with Praziquantel has reduced severe morbidities, however reinfection is common and subtle morbidities persist. Alternative control strategies such as vaccine-linked chemotherapy show great promise and warrant further development. This thesis describes vaccine development in schistosomiasis japonica, in conjunction with our recently concluded treatment-reinfection study of a Schistosoma japonicum-infected cohort in Leyte, Philippines (N=553). The promising vaccine candidate paramyosin remains under-evaluated due to challenges in large-scale recombinant production, and we address this need with a robust process to express and purify S. japonicum paramyosin (rSj97). Pilot scale production yielded 22.4 mg of >95% pure rSj97, with functional binding and structural properties similar to native paramyosin. Sera collected from the cohort one month post-treatment were analyzed for isotype-specific (IgA, IgE, IgG1, IgG4, total IgG) antibody responses to a panel of schistosome antigens (SWAP, rSj97, rSj67, rSj22) using a multiplexed bead-based assay. Repeated measures regression analysis with reinfection data up to 12 months post-treatment showed that IgE responses to rSj97 solely predicted resistance to reinfection (p=0.018), while IgG4 responses to all antigens associated with susceptibility, after adjusting for potential confounders. In combined IgE and IgG4 analysis to rSj97, individuals with only IgE responses had a 77% lower intensity of reinfection at 12 months post-treatment (p=0.016) compared to individuals with IgG4 but not IgE. Immunoscreening of an S. japonicum expression library for clones differentially recognized by the resistant but not susceptible subpopulation identified a novel vaccine candidate, Sj6-8. Sj6-8 was expressed in E. coli, and a similar repeated measures analysis demonstrated that IgE responses to rSj6-8 was marginally associated with resistance (p=0.065), predicting a 63% lower intensity of reinfection at 12 months post-treatment. Overall, this thesis further supports paramyosin as a leading vaccine candidate for schistosomiasis japonica, and our development of a pilot scale production process for rSj97 paves the way for further pre-clinical and eventual clinical testing of this promising vaccine candidate. Advisors/Committee Members: Kurtis, Jonathan (director), Knopf, Paul (reader), Friedman, Jennifer (reader), McGarvey, Stephen (reader), Reichner, Jonathan (reader).

Subjects/Keywords: vaccine

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APA (6^th Edition):

Jiz, M. A. I. L. (2009). Vaccine Development in Schistosomiasis japonica: Paramyosin As a Leading Candidate. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:175/

Chicago Manual of Style (16^th Edition):

Jiz, Mario Antonio II L. “Vaccine Development in Schistosomiasis japonica: Paramyosin As a Leading Candidate.” 2009. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:175/.

MLA Handbook (7^th Edition):

Jiz, Mario Antonio II L. “Vaccine Development in Schistosomiasis japonica: Paramyosin As a Leading Candidate.” 2009. Web. 25 Mar 2019.

Vancouver:

Jiz MAIL. Vaccine Development in Schistosomiasis japonica: Paramyosin As a Leading Candidate. [Internet] [Doctoral dissertation]. Brown University; 2009. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:175/.

Council of Science Editors:

Jiz MAIL. Vaccine Development in Schistosomiasis japonica: Paramyosin As a Leading Candidate. [Doctoral Dissertation]. Brown University; 2009. Available from: https://repository.library.brown.edu/studio/item/bdr:175/

15. Brown, Caitlin Westberg. Notch3 promotes anoikis resistance via expression of col4α2 in epithelial ovarian cancer.

Degree: PhD, Pathobiology, 2014, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:386266/

► Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The five-year survival rate of women diagnosed with stage IV high-grade serous epithelial ovarian cancer… (more)

▼ Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The five-year survival rate of women diagnosed with stage IV high-grade serous epithelial ovarian cancer is 19% (NCI). A strong tendency towards genomic instability, chemoresistance and a late diagnosis all contribute to the poor overall survival rate. Despite the development of new chemotherapeutics and novel delivery methods, this rate has not changed significantly since the 1970s, indicating a need for new therapeutic targets. The Notch signaling pathway has been implicated in tumorigenesis and cancer progression in several cancer types. However, the role of Notch signaling has also been shown to be highly context-dependent. The mechanism by which Notch3 promotes dissemination of epithelial ovarian tumors is currently an active area of study. The studies presented in this thesis characterize an in vitro cell model of the role of Notch3 promoting metastasis in EOC. This model was used to establish that Notch3 promotes invasion in the IGROV-1 cell line but does not appear to play a significant role in regulating migration, resistance to oxaliplatin or cell cycle alterations. Additionally, we found that Notch3 promotes anoikis resistance. We report a positive role for focal adhesion kinase as well as the downstream signaling kinases Akt and Erk 1/2 in promoting the anchorage-independent growth ovarian cancer cells. mRNA and protein levels of col4α2 are reduced when Notch3 levels are decreased and exogenous collagen IV supplementation can largely reverse the anoikis sensitivity. Reduction of col4α2 expression by siRNA induces cell death. High Notch3 expression levels correlate with higher col4α2 expression in human ovarian tumor samples. Our data thus expand on previous findings and highlight type IV collagen as a novel potential therapeutic target for metastatic epithelial ovarian cancer. Advisors/Committee Members: Freiman, Richard (Director), Boekelheide, Kim (Reader), Reichner, Jonathan (Reader), Zhitkovich, Anatoly (Reader), Zhang, Hong (Reader).

Subjects/Keywords: epithelial ovarian cancer

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APA (6^th Edition):

Brown, C. W. (2014). Notch3 promotes anoikis resistance via expression of col4α2 in epithelial ovarian cancer. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386266/

Chicago Manual of Style (16^th Edition):

Brown, Caitlin Westberg. “Notch3 promotes anoikis resistance via expression of col4α2 in epithelial ovarian cancer.” 2014. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:386266/.

MLA Handbook (7^th Edition):

Brown, Caitlin Westberg. “Notch3 promotes anoikis resistance via expression of col4α2 in epithelial ovarian cancer.” 2014. Web. 25 Mar 2019.

Vancouver:

Brown CW. Notch3 promotes anoikis resistance via expression of col4α2 in epithelial ovarian cancer. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:386266/.

Council of Science Editors:

Brown CW. Notch3 promotes anoikis resistance via expression of col4α2 in epithelial ovarian cancer. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386266/

16. Hutchins, Noelle A. The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal Endothelial Cell Dysfunction in Sepsis.

Degree: PhD, Pathobiology, 2013, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:320516/

► This dissertation focuses on the response of liver sinusoidal endothelial cells (LSECs) to experimental sepsis in order to better understand the pathologic processes contributing to… (more)

▼ This dissertation focuses on the response of liver sinusoidal endothelial cells (LSECs) to experimental sepsis in order to better understand the pathologic processes contributing to acute liver injury (ALI) and ultimately multiple organ dysfunction syndrome (MODS). Under homeostatic conditions, the liver doesn’t respond to microbial antigens that travel through the portal vein from the digestive tract. In this regard, LSECs, represent a unique EC population, believed to play a role in maintaining local immune tolerance, in part, through the expression of two tolerogenic molecules, Fas and programmed death ligand-1 (PD-L1). Although these two cell surface molecules initiate independent signaling cascades, their impact on LSEC function during sepsis is unknown. Thus, the central hypothesis of this work was that increased Fas expression on LSECs contributes to sepsis-induced liver injury, while elevated PD-L1 expression on LSECs attempts to sustain the immune tolerant state in the septic liver. This dissertation explores how these two cell surface molecules play a role on LSEC dysfunction in an animal sepsis model (cecal ligation and puncture [CLP]). Sepsis fosters an infiltration of leukocytes, which activate the sinusoidal endothelium, leading to an increase of adhesion molecule expression. Subsequently, we show that LSECs are susceptible to increased vascular permeability and undergo Fas-mediated apoptosis during sepsis by comparing CLP WT and CLP Fas-/- mice. Surprisingly, kupffer cells (KCs) appear to protect LSECs from further sepsis-induced injury by secreting IL-6, and engaging the endothelial IL-6 receptor. In contrast to our hypothesis, increased PD-L1 does not protect LSECs from sepsis-induced injury. PD-L1 gene deficiency in CLP animals actually proves to be beneficial to LSEC survival and permeability, essential aspects of EC function. PD-L1 gene deficiency also decreases STAT3 activation, which has been shown to protect ECs from endotoxin-injury. Unlike the suppression of Fas, which drives LSEC injury, KCs may mediate this PD-L1 driven effect. Overall, the results presented herein suggest that Fas and PD-L1 play important and unanticipated roles in LSEC dysfunction, which develops in response to sepsis, contributing to hepatic injury and/or organ dysfunction. Advisors/Committee Members: Ayala, Alfred (Director), Reichner, Jonathan (Reader), Sharma, Surendra (Reader), Shaw, Sunil (Reader), Stearns-Kurosawa, Deborah (Reader).

Subjects/Keywords: sepsis

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APA (6^th Edition):

Hutchins, N. A. (2013). The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal Endothelial Cell Dysfunction in Sepsis. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:320516/

Chicago Manual of Style (16^th Edition):

Hutchins, Noelle A. “The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal Endothelial Cell Dysfunction in Sepsis.” 2013. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:320516/.

MLA Handbook (7^th Edition):

Hutchins, Noelle A. “The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal Endothelial Cell Dysfunction in Sepsis.” 2013. Web. 25 Mar 2019.

Vancouver:

Hutchins NA. The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal Endothelial Cell Dysfunction in Sepsis. [Internet] [Doctoral dissertation]. Brown University; 2013. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:320516/.

Council of Science Editors:

Hutchins NA. The Multifaceted Roles of Fas and PD-L1 on Liver Sinusoidal Endothelial Cell Dysfunction in Sepsis. [Doctoral Dissertation]. Brown University; 2013. Available from: https://repository.library.brown.edu/studio/item/bdr:320516/

17. Stout, David Andrew. Analysis of nanostructuredve vs Lipopolysaccharide (LPS) Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using Traction Force Microscopy.

Degree: PhD, Biomedical Engineering, 2014, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:386196/

► Understanding the fundamental mechanisms, and forces, underlying cell migration holds the promise of effective approaches for treating diseases and promoting cellular transplantation. One such disease… (more)

▼ Understanding the fundamental mechanisms, and forces, underlying cell migration holds the promise of effective approaches for treating diseases and promoting cellular transplantation. One such disease is sepsis. During sepsis – a complex clinical syndrome that results from a harmful or damaging host response to infection – directed impairment has been shown of neutrophils to infectious foci and inadequate antimicrobial responses. In order to understand how sepsis affects neutrophil migration, we investigated the force generating characteristics and comparison between normal and septic neutrophil chemotaxis in a physiological relevant 3D mechanistically tractable system with the use of 3D FIDVC techniques. The development of a well controlled diffusion direct-viewing system was completed for chemotaxis studies, which allows one to overcome modern chemotaxis chamber obstacles. More compelling, we were able to successfully calculate the coefficient of diffusion of Rhodamine through five different concentrations of collagen as well as solve the governing diffusion equations to find the specific concentration along the surface of the cell. With the use of time-lapsed confocal microscopy and FIDVC we were able to probe the force generating chemotactic characteristic differences of naive and LPS activated neutrophils. We were able to show that in 3D, LPS activated neutrophils have greater deformation and displacement capabilities, while increasing their speed and decreasing their directness. Investigating the signaling pathways between fMLP and LPS our research suggests a molecule used in both GPCR and TRL4 pathways is being affected which may shed light in understanding sepsis. By introducing the study of mechanics in the investigation of sepsis, we have presented insight (force generation location and mobility) on how sepsis may alter neutrophil function that may not have been noticed by traditional biological assays. Advisors/Committee Members: Franck, Christian (Director), Reichner, Jonathan (Reader), Tripathi, Anubhav (Reader), Darling, Eric (Reader), Hammer, Daniel (Reader).

Subjects/Keywords: Traction Force Microscopy

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APA (6^th Edition):

Stout, D. A. (2014). Analysis of nanostructuredve vs Lipopolysaccharide (LPS) Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using Traction Force Microscopy. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386196/

Chicago Manual of Style (16^th Edition):

Stout, David Andrew. “Analysis of nanostructuredve vs Lipopolysaccharide (LPS) Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using Traction Force Microscopy.” 2014. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:386196/.

MLA Handbook (7^th Edition):

Stout, David Andrew. “Analysis of nanostructuredve vs Lipopolysaccharide (LPS) Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using Traction Force Microscopy.” 2014. Web. 25 Mar 2019.

Vancouver:

Stout DA. Analysis of nanostructuredve vs Lipopolysaccharide (LPS) Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using Traction Force Microscopy. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:386196/.

Council of Science Editors:

Stout DA. Analysis of nanostructuredve vs Lipopolysaccharide (LPS) Activated Neutrophil Chemotaxis in 3D Collagen Matrices Using Traction Force Microscopy. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386196/

18. Byrd, Angel Shree'. Abstract of, “Regulation of Human Neutrophil Functions by the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd, Ph.D., Brown University, May 2014.

Degree: PhD, Pathobiology, 2014, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:386316/

► Neutrophil-mediated host defense against pathogens includes the extrusion of a lattice of DNA and microbicidal enzymes known as Neutrophil Extracellular Traps (NETs). The receptor:ligand interactions… (more)

▼ Neutrophil-mediated host defense against pathogens includes the extrusion of a lattice of DNA and microbicidal enzymes known as Neutrophil Extracellular Traps (NETs). The receptor:ligand interactions and intracellular signaling mechanisms responsible for elaborating NETs were determined for the response to Candida albicans. Since the host response of extravasated neutrophils to mycotic infections within tissues necessitates contact with ECM, this study also identified a novel and significant regulatory role for the ubiquitous matrix component fibronectin (Fn) in NET release. We report that recognition of purified fungal pathogen-associated molecular pattern β-glucan by human neutrophils causes rapid (≤ 30 mins) homotypic aggregation and NET release by a mechanism that requires Fn. Alone, immobilized β-glucan induces reactive oxygen species (ROS) production but not NET release, whereas in the context of Fn, ROS production is suppressed and NETs are extruded. NET release to Fn + β-glucan is robust, accounting for 17.2 ± 3.4% of total DNA in the cell population. Release is dependent on β-glucan recognition by CR3 (CD11b/CD18), but not Dectin-1, or ROS. The process of NET release included filling of intracellular vesicles with nuclear material that was eventually extruded. We identify a role for ERK in homotypic aggregation and NET release. NET formation to C. albicans hyphae was also found to depend on β-glucan recognition by CR3, require Fn and ERK but not ROS, and results in hyphal destruction. We report a new regulatory mechanism of NETosis in which the extracellular matrix is a key component of the rapid anti-fungal response. We also report that neonatal neutrophils formed aggregates and released NETs rapidly and independent of ROS production. Providing additional evidence of the ROS independent mechanism of aggregation and NET release, neutrophils from Chronic Granulomatous Disease (CGD) patients formed large homotypic aggregates and released NETs to β-glucan and Fn. Therefore, the susceptibility of these immunocompromised populations to fungal infections may not be due to an inherent inability of neutrophils to aggregate and produce NETs in response to the fungal PAMP β-glucan. Ultimately, we hope innovative therapeutic approaches can mediate a regulatory balance in immunocompromised patients to improve health outcomes. Advisors/Committee Members: Reichner, Jonathan (Director), Gruppuso, Philip (Reader), Sanders, Jennifer (Reader), Frackelton, A. Raymond (Reader), Salomon, Arthur (Reader).

Subjects/Keywords: NEONATES

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APA (6^th Edition):

Byrd, A. S. (2014). Abstract of, “Regulation of Human Neutrophil Functions by the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd, Ph.D., Brown University, May 2014. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386316/

Chicago Manual of Style (16^th Edition):

Byrd, Angel Shree'. “Abstract of, “Regulation of Human Neutrophil Functions by the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd, Ph.D., Brown University, May 2014.” 2014. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:386316/.

MLA Handbook (7^th Edition):

Byrd, Angel Shree'. “Abstract of, “Regulation of Human Neutrophil Functions by the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd, Ph.D., Brown University, May 2014.” 2014. Web. 25 Mar 2019.

Vancouver:

Byrd AS. Abstract of, “Regulation of Human Neutrophil Functions by the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd, Ph.D., Brown University, May 2014. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:386316/.

Council of Science Editors:

Byrd AS. Abstract of, “Regulation of Human Neutrophil Functions by the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd, Ph.D., Brown University, May 2014. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386316/

19. Toussaint, Leon E. Invariant Natural Killer T Cell Development is Uniquely Regulated by Y-Chromosome Genes and SHIP-1.

Degree: PhD, Pathobiology, 2012, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:297571/

► The Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP-1) plays a critical role in regulating the phosphoinositide 3-kinases (PI3Ks) signaling pathway. PI3Ks are important for… (more)

Subjects/Keywords: Y-linked genes

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APA (6^th Edition):

Toussaint, L. E. (2012). Invariant Natural Killer T Cell Development is Uniquely Regulated by Y-Chromosome Genes and SHIP-1. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297571/

Chicago Manual of Style (16^th Edition):

Toussaint, Leon E. “Invariant Natural Killer T Cell Development is Uniquely Regulated by Y-Chromosome Genes and SHIP-1.” 2012. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:297571/.

MLA Handbook (7^th Edition):

Toussaint, Leon E. “Invariant Natural Killer T Cell Development is Uniquely Regulated by Y-Chromosome Genes and SHIP-1.” 2012. Web. 25 Mar 2019.

Vancouver:

Toussaint LE. Invariant Natural Killer T Cell Development is Uniquely Regulated by Y-Chromosome Genes and SHIP-1. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:297571/.

Council of Science Editors:

Toussaint LE. Invariant Natural Killer T Cell Development is Uniquely Regulated by Y-Chromosome Genes and SHIP-1. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297571/

20. Andrews, Christina. A Biophysical Analysis of Neutrophil Force Generation in a Biochemical Environment.

Degree: Biomedical Engineering, 2018, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:792823/

► Neutrophils are the most abundant circulating white blood cell in the human body, and play a crucial role in the innate immune response to infection… (more)

Subjects/Keywords: Immunology

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APA (6^th Edition):

Andrews, C. (2018). A Biophysical Analysis of Neutrophil Force Generation in a Biochemical Environment. (Thesis). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:792823/

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):

Andrews, Christina. “A Biophysical Analysis of Neutrophil Force Generation in a Biochemical Environment.” 2018. Thesis, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:792823/.

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

MLA Handbook (7^th Edition):

Andrews, Christina. “A Biophysical Analysis of Neutrophil Force Generation in a Biochemical Environment.” 2018. Web. 25 Mar 2019.

Vancouver:

Andrews C. A Biophysical Analysis of Neutrophil Force Generation in a Biochemical Environment. [Internet] [Thesis]. Brown University; 2018. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:792823/.

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

Council of Science Editors:

Andrews C. A Biophysical Analysis of Neutrophil Force Generation in a Biochemical Environment. [Thesis]. Brown University; 2018. Available from: https://repository.library.brown.edu/studio/item/bdr:792823/

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

21. O'Brien, Xian Marie. Innate Immune Functions of Human Polymorphonuclear Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1 Integrin Engagement and β-glucan, a Fungal Pathogen Associated Molecular Pattern.

Degree: PhD, Pathobiology, 2010, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:11088/

► Invasive fungal infections are emerging as a significant cause of morbidity and mortality, especially among the increasing immunosuppressed patient populations. Transition to a filamentous hyphal… (more)

▼ Invasive fungal infections are emerging as a significant cause of morbidity and mortality, especially among the increasing immunosuppressed patient populations. Transition to a filamentous hyphal morphology, which is not easily cleared by phagocytosis, correlates strongly with invasiveness and virulence. This dissertation explored the effects of β-glucan, a component of the pathogenic yeast cell wall, on human polymorphonuclear leukocyte (PMN) respiratory burst, migration and mechanosensing as mediated through the β2 integrin, CR3 (αMβ2). CR3 is a known β-glucan receptor via a lectin-like domain. These and other studies from our laboratory have shown that β-glucan accelerates chemotaxis of PMNs when added to a fibronectin (Fn) matrix. We show that immobilized β-glucan stimulates plasma membrane-associated respiratory burst, which is inhibited by Fn. β-glucan was shown to exhort its PMN priming effects through CR3 modulated in part through a system of β1-to-β2 integrin cross talk with VLA3 (α3β1) and VLA5 (α5β1). A putative mechanism through p38 MAPK and Lyn PTK is proposed. We show that PMN migration on the CR3 ligand fibrinogen is independent of substrate stiffness, unlike the β1-mediated migration of PMNs on Fn. Migration in the presence of soluble β-glucan significantly increased PMN polarity index and significantly reduced the percentage of PMNs that initiated a respiratory burst before reaching the chemoattractant source. Taken together, these data suggest that activation of β1 integrins and priming by β-glucan elaborated by a fungal infection may determine an inflammatory cell phenotype that is well suited to eliminate the virulent, filamentous form of fungi by accelerating chemotaxis towards the foci of infection while suppressing the premature release of oxidants until the neutrophil establishes direct multifocal contact with hyphae. Additionally, fluorescence resonance energy transfer (FRET) based reporter constructs for CR3 activation and avidity were generated that provide evidence for conformational changes in the cytoplasmic domains of CR3 during physiologic activation, as well priming with soluble β-glucan. We also extended this by developing a differentiated HL-60 system that allows for the tracking of CR3 dynamic regulation during relevant PMN cellular functions. Advisors/Committee Members: Reichner, Jonathan (Director), Atwood, Walter (Reader), Wessel, Gary (Reader), Jay, Tang (Reader), Jun, Yan (Reader).

Subjects/Keywords: respiratory burst

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APA (6^th Edition):

O'Brien, X. M. (2010). Innate Immune Functions of Human Polymorphonuclear Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1 Integrin Engagement and β-glucan, a Fungal Pathogen Associated Molecular Pattern. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:11088/

Chicago Manual of Style (16^th Edition):

O'Brien, Xian Marie. “Innate Immune Functions of Human Polymorphonuclear Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1 Integrin Engagement and β-glucan, a Fungal Pathogen Associated Molecular Pattern.” 2010. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:11088/.

MLA Handbook (7^th Edition):

O'Brien, Xian Marie. “Innate Immune Functions of Human Polymorphonuclear Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1 Integrin Engagement and β-glucan, a Fungal Pathogen Associated Molecular Pattern.” 2010. Web. 25 Mar 2019.

Vancouver:

O'Brien XM. Innate Immune Functions of Human Polymorphonuclear Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1 Integrin Engagement and β-glucan, a Fungal Pathogen Associated Molecular Pattern. [Internet] [Doctoral dissertation]. Brown University; 2010. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:11088/.

Council of Science Editors:

O'Brien XM. Innate Immune Functions of Human Polymorphonuclear Leukocytes As Mediated by the β2 Integrin, CR3, and Modulated by β1 Integrin Engagement and β-glucan, a Fungal Pathogen Associated Molecular Pattern. [Doctoral Dissertation]. Brown University; 2010. Available from: https://repository.library.brown.edu/studio/item/bdr:11088/

22. Toorie, Anika M. The role of hypothalamic Sirt1 in the regulation of the hypophysiotropic adrenal and thyroid axes.

Degree: PhD, Pathobiology, 2015, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:419479/

► Sirtuin 1 is a metabolic sensor that has a role in metabolic homeostasis in the periphery and at the central level. Its role in the… (more)

▼ Sirtuin 1 is a metabolic sensor that has a role in metabolic homeostasis in the periphery and at the central level. Its role in the periphery has been heavily studied and studies demonstrate peripheral Sirt1 in protecting against the development of obesity and mitigating adverse phenotypes that are associated with obesity, such as insulin resistance. Brain Sirt1’s role in energy balance is less established as studies have provided conflicting evidence regarding its role in energy homeostasis. Others and we demonstrated a role of Sirt1 in promoting a positive energy balance by affecting both food intake and energy expenditure. Findings from Dr. Nillni’s laboratory were amongst the first to reveal that Sirt1 functions in an orexigenic capacity, an effect that was mediated via the transcription factor FoxO1, and its actions on the central melanocortin system. The work described in this dissertation extends upon those earlier findings and elucidates the role of hypothalamus Sirt1 in the diet induced obese (DIO) condition. We demonstrate a novel regulation of the HPA axis by Sirt1 expressed in the hypothalamus paraventricular nucleus (PVN). The results reveal that Sirt1 is increased in the PVN of DIO rats and that this is associated with elevated basal corticosterone, which is known to promote a positive energy balance by instigating food intake. Inhibiting PVN Sirt1 activity resulted in a decrease in PVN prohormone convertase 2, which is one of the processing enzymes responsible for the processing of proCorticotropin releasing hormone into the bioactive CRH molecule, as well as the amount of CRH targeted to the median eminence. These effects were associated with reduced basal corticosterone; alongside an increase in insulin that we posit may precede enhanced insulin sensitivity. We also show that Sirt1 is increased in the hypothalamus arcuate nucleus of DIO rats and that central inhibition of Sirt1 activity is sufficient to reduce body weight gain in DIO rats due to an increase in HPT activity and energy expenditure. The findings presented here reveal a role of ARC and PVN Sirt1 in promoting metabolic dysfunction and suggests hypothalamic Sirt1 inhibition as an effective target against obesity. Advisors/Committee Members: Nillni, Eduardo (Director), Reichner, Jonathan (Reader), Oancea, Elena (Reader), Marshall, John (Reader), Wardlaw, Sharon (Reader), Nillni, Eduardo (Director), Reichner, Jonathan (Reader), Oancea, Elena (Reader), Marshall, John (Reader), Wardlaw, Sharon (Reader).

Subjects/Keywords: diet induced obesity

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APA (6^th Edition):

Toorie, A. M. (2015). The role of hypothalamic Sirt1 in the regulation of the hypophysiotropic adrenal and thyroid axes. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419479/

Chicago Manual of Style (16^th Edition):

Toorie, Anika M. “The role of hypothalamic Sirt1 in the regulation of the hypophysiotropic adrenal and thyroid axes.” 2015. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:419479/.

MLA Handbook (7^th Edition):

Toorie, Anika M. “The role of hypothalamic Sirt1 in the regulation of the hypophysiotropic adrenal and thyroid axes.” 2015. Web. 25 Mar 2019.

Vancouver:

Toorie AM. The role of hypothalamic Sirt1 in the regulation of the hypophysiotropic adrenal and thyroid axes. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:419479/.

Council of Science Editors:

Toorie AM. The role of hypothalamic Sirt1 in the regulation of the hypophysiotropic adrenal and thyroid axes. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419479/

23. Johnson, Courtney Michele. Molecular Mechanisms Underlying The Human Neutrophil Response To Fungal Beta-Glucan In The Context Of The Extracellular Matrix Protein Fibronectin.

Degree: PhD, Pathobiology, 2015, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:419450/

► Complement Receptor 3 (CR3), a β2 integrin found on neutrophils, plays an important role in fungal recognition and immune response. Co-ligation of CR3 with fibronectin… (more)

▼ Complement Receptor 3 (CR3), a β2 integrin found on neutrophils, plays an important role in fungal recognition and immune response. Co-ligation of CR3 with fibronectin (Fn), an ubiquitous extracellular matrix component, at the I-domain and β-glucan (B), a glucose polymer found in fungal cell walls, at the lectin-like domain is possible due to spatially distinct locations. Dual ligation of CR3 with Fn+B induces homotypic aggregation of primed neutrophils, a response representative of the immune cells encounter with fungi within tissues and that can be blocked by anti-CR3 antibody. Previous findings have shown that CR3-mediated DNA Neutrophillic Extracellular Traps (NETS) coincide with PMN aggregates. To understand the molecular mechanisms of how CR3 coordinates these neutrophil responses, this thesis explores the role of the integrins CR3 as well as the β1 integrin family members VLA3 and VLA5. Using antibody blockade and receptor-FRET, we unexpectedly discovered a CR3-mediated required role for VLA3, the canonical laminin receptor, in aggregate formation. The role of VLA3 in aggregate formation was specific as blockade of other β1 integrin family members such as VLA5, the canonical Fn receptor, failed to prevent aggregation. Exploring the role of VLA5, we were able to show a decrease in overall VLA5 activity on Fn+B and by using an activating anti-VLA5 antibody, that active inhibition of VLA5 activity is necessary for aggregate formation. In assessing NETs formation, we discovered that unlike aggregate formation, VLA5 and CR3 are necessary for NET formation, where VLA3 is not. Furthermore, activation of VLA5 with the activating VLA5 antibody does not inhibit NET formation. Finally, a correlative signaling role for p-ERK and p-GSK-3β was determined in the neutrophil responses to β-glucan and Fn but not to either alone. Within this thesis, a novel, complex and temporally regulated cross-talk pathway was uncovered in which dual ligation of CR3 signals the differential regulation of individual β1 integrins not often associated with anti-fungal activity. Furthermore, it was discovered that NETosis and aggregation are controlled by the activation state of distinct β1 integrins, VLA5 and VLA3, respectively. Advisors/Committee Members: Reichner, Jonathan (Director), Bowen, Wayne (Reader), Bliss, Joseph (Reader), Sanders, Jennifer (Reader), Luscinskas, Francis (Reader), Fast, Loren (Director).

Subjects/Keywords: Complement Receptor 3

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APA (6^th Edition):

Johnson, C. M. (2015). Molecular Mechanisms Underlying The Human Neutrophil Response To Fungal Beta-Glucan In The Context Of The Extracellular Matrix Protein Fibronectin. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:419450/

Chicago Manual of Style (16^th Edition):

Johnson, Courtney Michele. “Molecular Mechanisms Underlying The Human Neutrophil Response To Fungal Beta-Glucan In The Context Of The Extracellular Matrix Protein Fibronectin.” 2015. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:419450/.

MLA Handbook (7^th Edition):

Johnson, Courtney Michele. “Molecular Mechanisms Underlying The Human Neutrophil Response To Fungal Beta-Glucan In The Context Of The Extracellular Matrix Protein Fibronectin.” 2015. Web. 25 Mar 2019.

Vancouver:

Johnson CM. Molecular Mechanisms Underlying The Human Neutrophil Response To Fungal Beta-Glucan In The Context Of The Extracellular Matrix Protein Fibronectin. [Internet] [Doctoral dissertation]. Brown University; 2015. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:419450/.

Council of Science Editors:

Johnson CM. Molecular Mechanisms Underlying The Human Neutrophil Response To Fungal Beta-Glucan In The Context Of The Extracellular Matrix Protein Fibronectin. [Doctoral Dissertation]. Brown University; 2015. Available from: https://repository.library.brown.edu/studio/item/bdr:419450/

24. Crane, Meredith J. Innate Immune Events Promoting Antiviral Defense during MCMV Infection.

Degree: PhD, Pathobiology, 2012, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:297563/

► The studies presented in this thesis investigated innate immune events in the liver during acute infection with murine cytomegalovirus (MCMV). While many responses that occur… (more)

▼ The studies presented in this thesis investigated innate immune events in the liver during acute infection with murine cytomegalovirus (MCMV). While many responses that occur in the liver are well understood, the mechanism of viral sensing is not known. The first set of studies investigated whether nucleic acid-sensing TLRs mediate MCMV recognition and promote liver antiviral responses. Mice that cannot signal through these TLRs due to a point mutation in UNC93B1 were infected to assess downstream immune responses. Infected UNC93B1-deficient mice were severely impaired in proinflammatory cytokine production, with delayed accumulation of plasmacytoid dendritic cells and natural killer cells in the liver, although T cell responses were intact. Additionally, these mice had more severe liver pathology and increased serum ALT levels. Ultimately, UNC93B1-deficient mice were significantly impaired in their ability to clear the virus from the liver. Thus, signaling through nucleic acid-sensing TLRs is necessary for MCMV recognition and downstream responses in the liver. In addition to MCMV recognition, early infiltration of monocytes to the liver is critical in promoting antiviral defense during acute infection. A second set of studies investigated the role of the chemokine receptor CCR2 in recruiting inflammatory monocytes from the bone marrow to peripheral sites, such as the liver, during MCMV infection. It was hypothesized that CCR2 activation is required for inflammatory monocyte mobilization from the bone marrow. In MCMV-infected CCR2-deficent mice, inflammatory monocytes accumulated in the bone marrow and were absent in the circulation. In wild type mice, it was also found that F4/80+ cells in the bone marrow produce CCR2 ligands in an IFN-α-dependent manner concurrent with monocyte egress. These results suggest that early MCMV recognition induces IFN-α, which signals CCR2 ligand production in the bone marrow to promote the egress of CCR2-expressing inflammatory monocytes to peripheral sites of infection. Together, these studies contribute to our understanding of the early immune events that promote liver antiviral defense during acute MCMV infection. Advisors/Committee Members: Salazar-Mather, Thais (Director), Reichner, Jonathan (Reader), Brossay, Laurent (Reader), Atwood, Walter (Reader), Kurt-Jones, Evelyn (Reader).

Subjects/Keywords: MCMV

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APA (6^th Edition):

Crane, M. J. (2012). Innate Immune Events Promoting Antiviral Defense during MCMV Infection. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297563/

Chicago Manual of Style (16^th Edition):

Crane, Meredith J. “Innate Immune Events Promoting Antiviral Defense during MCMV Infection.” 2012. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:297563/.

MLA Handbook (7^th Edition):

Crane, Meredith J. “Innate Immune Events Promoting Antiviral Defense during MCMV Infection.” 2012. Web. 25 Mar 2019.

Vancouver:

Crane MJ. Innate Immune Events Promoting Antiviral Defense during MCMV Infection. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:297563/.

Council of Science Editors:

Crane MJ. Innate Immune Events Promoting Antiviral Defense during MCMV Infection. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297563/

25. Ramirez, Teresa. Contributions of Insulin Resistance, Endoplasmic Reticulum Stress, and Ceramides in Alcoholic Liver Disease.

Degree: PhD, Molecular Pharmacology, Physiology, and Biotechnology, 2014, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:386183/

► Background: Chronic alcoholic liver disease is associated with hepatic insulin resistance, inflammation, oxidative and ER stress, mitochondrial dysfunction, and DNA damage. Peroxisome proliferator activated receptor… (more)

▼ Background: Chronic alcoholic liver disease is associated with hepatic insulin resistance, inflammation, oxidative and ER stress, mitochondrial dysfunction, and DNA damage. Peroxisome proliferator activated receptor (PPAR) agonists are insulin sensitizers that have anti-inflammatory/anti-oxidant effects. Hypothesis: We hypothesized that treatment with insulin sensitizer agents, can restore hepatic insulin signaling in ethanol exposed livers and will reduce ceramide accumulation and ER stress. Herein, we furthered our investigations by characterizing the histological and ultrastructural changes mediated by PPAR agonist rescue of alcohol-induced steatohepatitis. Methods: Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets, rats were treated with vehicle, or a PPAR-alpha, PPAR-delta, or PPAR-gamma agonist twice weekly by i.p. injection. Results: Ethanol-fed rats developed steatohepatitis with disordered hepatic chord architecture, mega-mitochondria, disruption of the RER, increased apoptosis, and increased 4-hydroxynonenal (HNE) and 3-nitrotyrosine (NTyr) immunoreactivity. PPAR-delta and PPAR-gamma agonists reduced the severity of steatohepatitis, and restored the hepatic chord-like architecture, mitochondrial morphology, and RER organization, and the PPAR-delta agonist significantly reduced hepatic HNE. On the other hand, prominent RER tubule dilation, which could reflect ER stress, persisted in ethanol-exposed, PPAR-gamma treated, but not PPAR-delta treated livers. The PPAR-alpha agonist exacerbated both steatohepatitis and formation of mega-mitochondria, and it failed to restore RER architecture or lower biochemical indices of oxidative stress. Conclusion: Improved hepatic insulin responsiveness and decreased inflammation resulting from PPAR-delta or PPAR-gamma agonist treatments of alcohol-induced steatohepatitis are likely mediated by enhanced signaling through metabolic pathways with attendant reductions in ER stress, oxidative stress, and mitochondrial dysfunction. Advisors/Committee Members: de la Monte, Suzanne (Director), Wands, Jack (Reader), Hai, Chi-Ming (Reader), Reichner, Jonathan (Reader), Wan, Yinsheng (Reader).

Subjects/Keywords: Alcoholic liver disease; Experimental model; PPAR agonists; Steato-hepatitis; Insulin Resistance; Histopathology; Electron microscopy; ER stress

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APA (6^th Edition):

Ramirez, T. (2014). Contributions of Insulin Resistance, Endoplasmic Reticulum Stress, and Ceramides in Alcoholic Liver Disease. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:386183/

Chicago Manual of Style (16^th Edition):

Ramirez, Teresa. “Contributions of Insulin Resistance, Endoplasmic Reticulum Stress, and Ceramides in Alcoholic Liver Disease.” 2014. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:386183/.

MLA Handbook (7^th Edition):

Ramirez, Teresa. “Contributions of Insulin Resistance, Endoplasmic Reticulum Stress, and Ceramides in Alcoholic Liver Disease.” 2014. Web. 25 Mar 2019.

Vancouver:

Ramirez T. Contributions of Insulin Resistance, Endoplasmic Reticulum Stress, and Ceramides in Alcoholic Liver Disease. [Internet] [Doctoral dissertation]. Brown University; 2014. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:386183/.

Council of Science Editors:

Ramirez T. Contributions of Insulin Resistance, Endoplasmic Reticulum Stress, and Ceramides in Alcoholic Liver Disease. [Doctoral Dissertation]. Brown University; 2014. Available from: https://repository.library.brown.edu/studio/item/bdr:386183/

26. Longato, Lisa. Pathogenic mechanisms and consequences of steatohepatitis.

Degree: PhD, Pathobiology, 2012, Brown University

URL: https://repository.library.brown.edu/studio/item/bdr:297566/

► The mechanisms by which steatohepatitis in alcoholic (ALD) or non-alcoholic (NAFLD) fatty liver disease becomes progressive and advances to stages of fibrosis, cirrhosis, and liver… (more)

▼ The mechanisms by which steatohepatitis in alcoholic (ALD) or non-alcoholic (NAFLD) fatty liver disease becomes progressive and advances to stages of fibrosis, cirrhosis, and liver failure are poorly understood. We hypothesize that shifts in hepatic lipid composition that favor the accumulation of bioactive, toxic lipids promote insulin resistance, which leads to increased mitochondrial dysfunction, oxidative stress, inflammation, cell injury and death. The overarching goal of this research was to examine the roles of aberrant ceramide generation and accumulation in the pathogenesis of progressive steatohepatitis in ALD and NAFLD in both humans and experimental models. Using molecular and biochemical approaches, we found that both chronic high fat and alcohol feeding significantly up-regulated pro-ceramide gene expression and enzymatic activity via several pathways. Furthermore, these effects were associated with increased hepatic insulin resistance. Parallel studies in livers from patients with advanced ALD highlighted similar, but more severe changes involving pro-ceramide metabolism as well as insulin resistance, indicating the relevance of these findings with respect to the human disease. In vitro experiments using hepatocellular cell lines or precision-cut liver slice cultures demonstrated that: 1) exogenous exposure to short-chain ceramides impairs insulin signaling, mitochondrial function, and energy metabolism; 2) treatment with chemical inhibitors of pro-ceramide enzymes partially reverse the hepatotoxic effects of steatohepatitis. Overall, these results indicate that ceramide can serve as a lipid mediator of injury and insulin resistance in both ALD and NAFLD-associated steatohepatitis. Furthermore, the results suggest that, in both conditions, therapeutic strategies for preventing disease progression must be multi-pronged to support insulin responsiveness and inhibit toxic lipid accumulation and attendant tissue damage mediated by ER stress, mitochondrial dysfunction, and inflammation. Advisors/Committee Members: De la Monte, Suzanne (Director), Gruppuso, Philip (Reader), Kurtis, Jonathan (Reader), Reichner, Jonathan (Reader), Akhlaghi, Fatemeh (Reader).

Subjects/Keywords: NAFLD

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

APA (6^th Edition):

Longato, L. (2012). Pathogenic mechanisms and consequences of steatohepatitis. (Doctoral Dissertation). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:297566/

Chicago Manual of Style (16^th Edition):

Longato, Lisa. “Pathogenic mechanisms and consequences of steatohepatitis.” 2012. Doctoral Dissertation, Brown University. Accessed March 25, 2019. https://repository.library.brown.edu/studio/item/bdr:297566/.

MLA Handbook (7^th Edition):

Longato, Lisa. “Pathogenic mechanisms and consequences of steatohepatitis.” 2012. Web. 25 Mar 2019.

Vancouver:

Longato L. Pathogenic mechanisms and consequences of steatohepatitis. [Internet] [Doctoral dissertation]. Brown University; 2012. [cited 2019 Mar 25]. Available from: https://repository.library.brown.edu/studio/item/bdr:297566/.

Council of Science Editors:

Longato L. Pathogenic mechanisms and consequences of steatohepatitis. [Doctoral Dissertation]. Brown University; 2012. Available from: https://repository.library.brown.edu/studio/item/bdr:297566/

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