Browsing by Subject "Proliferation"
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Item Dietary and Cellular Mechanisms Regulating Hepatocyte Proliferation and Cancer(2017-08) Ploeger, JonathanObesity is well-documented to promote the development of nonalcoholic fatty liver disease (NAFLD) including its more advanced stages such as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma (HCC). While metabolic perturbations describing obesogenic progression from NAFLD to HCC have largely been investigated, our knowledge of the role lipolysis plays in this process is scant. This research project is aimed at understanding the role fasting lipid metabolism plays in pathologic features of carcinogenesis as well as synergistically combining with lifestyle factors to prevent obesity driven progression of NAFLD to HCC. To elucidate these features, we employed two seminal studies. The first study characterized the role of adipose triglyceride lipase (ATGL) in limiting a major cell cycle regulator, cyclin D1, and hepatocellular proliferation both in vitro and in vivo. We show that lipid catabolism via ATGL antagonizes cell proliferation. Additionally, we recapitulate these findings using a partial hepatectomy model to drive hepatocellular proliferation in vivo. In the second study, we conduct a long-term carcinogenesis study that examines the role of dietary fat composition and lifestyle factors that promote fasting lipid metabolism. Animals were calorically restricted (CR) or exposed to regular endurance exercise. Using the hepatic carcinogen diethylnitrosamine (DEN), we show CR prevents hepatic tumor formation independent of dietary fat composition. RNA sequencing of non-transformed liver tissues revealed changes in metabolic pathways and reduced inflammation, cytokine production, stellate cell activation and migration, and genes associated with liver injury and oncogenesis. Taken together, fasting hepatic lipid metabolism plays a significant role in mitigating proliferative effects often associated with overconsumption of calories. Furthermore, lifestyle factors that promote lipolysis in the liver robustly protected mice from developing tumors. Further investigation is warranted to define the molecular mechanisms ATGL plays in limiting hepatic proliferation as well as characterizing the role of ATGL and fasting in hepatic tumorigenesis.Item Differential modulation of arterial vs venous smooth muscle cell proliferation and migration by hypoxia and hypoxia inducible endothelial cell growth factors.(2011-09) Chanakira, AliceDespite intensive research studies, theories have yet to focus on the contribution of hypoxia to patency differences observed clinically between arterial vs. venous grafts. This study investigates the differential hypoxic response of endothelial cell (EC) derived growth factor on modulation of smooth muscle cell (SMC) proliferation and migration under hypoxia and its contribution to graft patency. Our study shows differential regulation of arterial vs. venous smooth muscle cell proliferation and migration under hypoxia. Initiation of SMC proliferation under hypoxia (<5% O2) occurred only after incubation with hypoxic endothelial cell conditioned media (H-ECM). After investigating several possible growth factors in the H-ECM that may be responsible for SMC proliferation, the greatest difference was observed in vascular endothelial growth factor (VEGF-A) and platelet derived growth factor homodimer B (PDGF-BB) expression. Under hypoxia, two-fold increase in VEGF-A was observed in arterial derived SMC (A-SMC) in comparison to venous derived (V-SMC), which showed no significant change. V-SMC showed higher vascular endothelial growth factor receptor -2 (VEGFR-2) expression under hypoxia, while A-SMC had significantly lower (p<0.05) receptor expression. Incubation with VEGFR-2 neutralizing antibody / platelet derived growth factor receptor (PDGFR) antagonist in V-SMC prior to addition of H-ECM resulted in decreased proliferation. A-SMC proliferation under hypoxia did not decrease with incubation of VEGFR-2 neutralizing antibody but did decrease upon PDGFR antagonist incubation. Proliferation in A-SMC and V-SMC was regulated by an ERK1/2 dependant mechanism with V-SMC showing greater ERK1/2 expression under hypoxia upon addition of hypoxic endothelial cell conditioned media. Our work was also focused on investigating the impact of hypoxia on smooth muscle cell migration. To summarize our work, we determined that SMC migration was occurring via an autocrine and paracrine mechanism under hypoxia. Migration in V-SMC under hypoxia was regulated via VEGFR-1 since there was an induction in VEGFR-1 expression under hypoxia and migration in V-SMC decreased upon neutralization with a VEGFR-1 antibody. V-SMC migration was also regulated by PDGF-BB since there was a partial reduction in V-SMC migration under hypoxia upon neutralization with PDGF-BB antibody. Migration in A-SMC was induced more by PDGF-BB since neutralization with PDGF-BB antibody decreased A-SMC migration to basal levels. In conclusion, our studies illustrate that origin of cellular growth factors play an important role in how the pathology of a disease develops. Therefore, combination therapies focusing on the use of anti-VEGFR-1 antagonist to combat migration and anti VEGFR-2 and PDGFR รข to combat proliferation, would work best to help alleviate intimal hyperplasia, a result of smooth muscle cell migration and proliferation in venous derived grafts and surgical interventions.Item Identification of Putative Fatty Acid Binding Protein 4 Receptors on Breast Cancer Epithelial Cells(2023-05) Chen, DongmeiFatty acid binding protein 4 (FABP4) is a small 15-kDa cytoplasmic lipid carrier protein regulating fatty acid trafficking and metabolism. It is one of the most abundant proteins in mature adipocytes and can be secreted into the extracellular environment upon lipolytic stimulus, functioning as an adipokine. Elevated circulating FABP4 levels have been associated with obesity-related and inflammation-related diseases. Recent studies have indicated FABPP4 as a potential biomarker in cancer diagnosis and prognosis. FABP4 upregulation or exogenous FABP4 (eFABP4) administration has been found to promote cancer growth, invasion and metastasis, while FABP4 inhibition reduced cancer progression. Understanding the molecular mechanism underlying FABP4 effects in cancer is critical for developing anticancer drugs. Although exogenous FABP4 has been found to exert pro-tumorigenic effects, there is no known FABP4 receptor that transduces its signaling into intracellular responses. Identifying a FABP4 receptor would be significant for targeting FABP4 in cancers. Furthermore, although fatty acids have been found to be essential in FABP4 function, the mechanisms explaining their collaboration remain largely unknown. This thesis aims to identify putative FABP4 receptors on cancer cell plasma membrane to understand FABP4 signaling in breast cancer cells. Our work reveals that eFABP4 binds to the extracellular domain of desmoglein 2 to mediate breast cancer epithelial cell growth via an ERK-NRF2 axis, suggesting desmoglein 2 as a FABP4 receptor. We also find that fatty acids enhance the interaction between FABP4 and desmoglein 2, which may explain why non-fatty acid binding mutants of FABP4 abolish FABP4 effects and support the role of fatty acids in FABP4 signaling. In conclusion, our findings provide new insights into the mechanism of FABP4 in the development and progression of obesity-associated cancers.Item Maintenance of immune fitness during reconstitution from T cell lymphopenia by CD4-positive, CD25-positive, and Foxp3-positive regulatory T cells.(2009-07) Winstead, Colleen JeanWork presented in this doctoral thesis focuses on the role of regulatory T cells (Tregs) in controlling T cell homeostasis and emergence of autoimmunity during immune reconstitution from lymphopenia. It is recognized that lymphopenia may be a common trigger of many autoimmune diseases due to oligoclonal expansion of self-reactive T cells with an effector phenotype. It is also a clinical fact that autoimmunity is often associated with immune deficiency and poor responsiveness to vaccines and infections. Research supporting work presented in chapter 2 of this thesis was based on the hypothesis that poor Treg function may play a central role in these phenomena. This work, published in June of 2008 in the Journal of Immunology, clearly demonstrated that Tregs selectively restrain one specific form of lymphopenia-induced proliferation characterized by burst-like cell cycle activity and effector T cell differentiation (spontaneous proliferation). The spontaneous form of lymphopenia-induced proliferation is the likely source of oligoclonal expansion of self-reactive T cells that drive autoimmunity. Work presented in chapter 3 of this thesis addresses the hypothesis that such oligoclonal expansion by a few T cell clones consumes resources away from the rest of the T cell population, which ultimately results in loss of T cell diversity. Using the technique of T cell adoptive transfer, we measured immune responses to infection with the gram negative bacteria Listeria monocytogenes in lymphopenic mice reconstituted in the presence or absence of Tregs by analysis of T cell receptor (TCR) Vbeta chain usage and repertoire sampling using Vbeta-Jbeta chain TCR spectratyping and magnetic bead enrichment with specific major histocompatibility (MHC) class I and II tetramers. Experimental results suggest that the presence of Tregs during immune reconstitution preserves TCR structural diversity and allows for more accumulation of pathogen-associated antigen-specific T cells in secondary lymphoid tissues following clearance of the infection. This result may otherwise seem paradoxical as Tregs are typically thought of as generalized suppressors of the immune system. Regardless, we believe this unappreciated ability to maintain T cell homeostasis through preservation of peripheral diversity will shed considerable insight into the role of Tregs in the immune system, vaccine responsiveness, pathogenesis of autoimmunity, and immune senescence.