Life Sciences Commons^™

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations & Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Nutrient Sensing Pathways Mediating Igfbp1 Phosphorylation In Fgr, Shapnil Bhuiyan

Electronic Thesis and Dissertation Repository

Impairment of fetal oxygen levels and nutrient delivery contributes to fetal growth restriction (FGR), which affects 20% of pregnancies. Such cellular stress induces hepatic Insulin-like Growth Factor Binding Protein 1 (IGFBP1) phosphorylation, which sequesters Insulin-like Growth Factor 1 (IGF-I) and markedly reduces fetal growth signaling. IGFBP1 hyperphosphoryaltion in hypoxia is mediated through the mTOR signaling pathway and through the Amino Acid Response (AAR) pathway during amino acid deprivation. Hypoxia stimulates upstream mTORC1 regulators, AMPK and REDD1 which are well-established upstream regulators of one of the two mTOR complexes, mTORC1. The molecular mechanisms by which upstream mTORC1-driven processes regulate IGFBP1 phosphorylation …

Developing Droplet Based 3d Cell Culture Methods To Enable Investigations Of The Chemical Tumor Microenvironment, Jacqueline A. De Lora

Biomedical Sciences ETDs

Adaptation of cancer cells to changes in the biochemical microenvironment in an expanding tumor mass is a crucial aspect of malignant progression, tumor metabolism, and drug efficacy. In vitro, it is challenging to mimic the evolution of biochemical gradients and the cellular heterogeneity that characterizes cancer tissues found in vivo. It is well accepted that more realistic and controllable in vitro 3D model systems are required to improve the overall cancer research paradigm and thus improve on the translation of results, but multidisciplinary approaches are needed for these advances. This work develops such approaches and demonstrates that new droplet-based cell-encapsulation …

Investigating Smoke Exposure And Chronic Obstructive Pulmonary Disease (Copd) With A Calibrated Agent Based Model (Abm) Of In Vitro Fibroblast Wound Healing., James A. Ratti

Theses and Dissertations

COPD is characterized by tissue inflammation and impaired remodeling that suggests fibroblast maintenance of structural homeostasis is dysregulated. Thus, we performed in vitro wound healing experiments on normal and diseased human lung fibroblasts and developed an ABM of fibroblasts closing a scratched monolayer using NetLogo to evaluate differences due to COPD or cigarette smoke condensate exposure. This ABM consists of a rule-set governing the healing response, accounting for cell migration, proliferation, death, activation and senescence rates; along with the effects of heterogeneous activation, phenotypic changes, serum deprivation and exposure to cigarette smoke condensate or bFGF. Simulations were performed to calibrate …

Priming Cardiovascular Stem Cells For Transplantation Using Short-Term Hypoxia, Ivan Hernandez

Electronic Theses, Projects, and Dissertations

Conventional medical treatments fail to address the underlying problems associated with the damage inflicted by a coronary event. Thus, the long-term prognosis of patients admitted for heart failure is disheartening, with reported survival rates of 25 percent. Recent advances in stem cell research highlight the potential benefits of autologous stem cell transplantation for stimulating repair in heart tissue. However, a majority of those suffering from cardiovascular diseases are older adults whose autologous cells no longer possess optimum functional capacity. Additional work is needed to identify the optimal cell types or conditions that will promote cardiovascular regeneration across all age groups. …

The Physiological Stress Response Caused By Hypoxia And Reperfusion Injury In Striped Bass (Morone Saxatilis) And Nile Tilapia (Oreochromis Niloticus), Amanda C. Reynolds

Electronic Theses and Dissertations

Approximately five million people in the United States are affected by cardiovascular related diseases yearly contributing to 300,000 annual deaths, making CVD the leading cause of mortality worldwide. It has been suggested that apoptosis (programmed cell death) contributes to the pathogenesis of cardiovascular diseases. When blood flow is reduced or cut off from the heart, usually by a thrombus, this results in oxygen deprivation (hypoxia) to the cardiomyocytes (heart cells). In response to this hypoxic stress, cardiomyocytes will undergo apoptosis. Since many species of fish can survive levels of hypoxia that would be fatal to mammals, fish are an ideal …

Hypoxia-Sensitive Gene Expression In The Gastrocnemius Muscle Following Chronic Hind Limb Ischemia, Andrew Tilton

Biological Sciences

Chronic ischemia, caused by the formation atherosclerotic plaque occlusions in major conduit arteries, is the leading cause of morbidity and mortality in western societies. Vascular remodeling can help compensate for the adverse effects of atherosclerotic plaque formation. Vascular remodeling relies heavily on vascular endothelial growth factor (VEGF), a critical protein that contributes to all forms of vascular formation and remodeling including angiogenesis, arteriogenesisand vasculogenesis. VEGF itself is up-regulated by the transcription factor, hypoxia inducible factor 1 alpha (HIF-1α), which becomes activated in low oxygen environments.

Through the use of animal chronic hindlimb ischemia models, these genes can be evaluated as …