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TESTING MICE AT RISK OF PANCREATIC CANCER FOR ALTERED PROTEIN PATHWAYS FOUND IN DIABETES
Title
TESTING MICE AT RISK OF PANCREATIC CANCER FOR ALTERED PROTEIN PATHWAYS FOUND IN DIABETES.
Creator
Cheung, Henley, Altomare, Deborah A., University of Central Florida
Abstract / Description
Pancreatic cancer is nearly asymptomatic, which can result in extensive grow and even metastasis to other organs before detection. When diagnosed at a late stage, the survival rate is 3%. Early detection is therefore the key to treating pancreatic cancer. Diabetes was identified as a risk factor for the development of pancreatic cancer, but the mechanism remains unknown. In this project, the objective was to delineate a link between diabetes and pancreatic cancer by examining their shared...
Show morePancreatic cancer is nearly asymptomatic, which can result in extensive grow and even metastasis to other organs before detection. When diagnosed at a late stage, the survival rate is 3%. Early detection is therefore the key to treating pancreatic cancer. Diabetes was identified as a risk factor for the development of pancreatic cancer, but the mechanism remains unknown. In this project, the objective was to delineate a link between diabetes and pancreatic cancer by examining their shared protein signaling pathways. In a previous study, hyper-activation of AKT1 resulted in a pre-diabetic phenotype and also increased upregulation of downstream phosphorylated mTOR and phosphorylated p70S6 kinase. More recently, mice with mutations that hyper-activated AKT1 and KRAS showed a significantly higher blood glucose level compared to littermate matched wild-type, mutant AKT1, or mutant KRAS mice. Interestingly, mice with a combination of mutations that hyper-activated AKT1 and KRAS also showed faster development of pancreatic cancer compared to these other groups of littermate mice. Toward determining a molecular basis for the crosstalk between AKT1 and KRAS, pancreas and liver tissues were collected from all four groups of mice including wild-type, mutant AKT1, mutant KRAS, and mice with dual AKT1/KRAS hyper-activation. One strategy was to examine expression and/or phosphorylation of downstream protein signaling crosstalk by analysis of p70S6K using Western Blots. Erk 1/2 proteins were also tested as downstream proteins of KRAS to provide a molecular view of the individual and cooperative roles of AKT1 and KRAS in the mouse models. A potential feedback mechanism to affect insulin receptor signaling in the pancreas was examined using enzyme-linked immunosorbent assays (ELISA). A significant decrease in insulin receptor phosphorylation, possibly contributing to insulin resistance, was found when mice had mutant hyper-activated KRAS. Contrary to the original expectations, mice with combined mutations of AKT1 and KRAS may contribute to the accentuated diabetic phenotype by targeting two different points in the AKT and KRAS protein signaling pathways. The information can help understand the relationship between glucose metabolism, diabetes, and pancreatic cancer development. By thoroughly studying the interactions between targets in the AKT1/KRAS signaling pathways, key molecular events that induce metabolic changes and potentially early biomarkers may lead to an improved understanding of risk and/or detection of pancreatic cancer.
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Date Issued
2017
Identifier
CFH2000273, ucf:45895
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000273
EFFECTS OF DIETARY FACTORS ON THE INCIDENCE AND PROGRESSION OF NON-ALCOHOLIC FATTY LIVER DISEASE
Title
EFFECTS OF DIETARY FACTORS ON THE INCIDENCE AND PROGRESSION OF NON-ALCOHOLIC FATTY LIVER DISEASE.
Creator
Lessans, Spencer L, Altomare, Deborah A., University of Central Florida
Abstract / Description
Non-alcoholic fatty liver disease (NAFLD) is a liver disorder linked to obesity that is rapidly increasing in incidence worldwide. It is a disorder that ranges in severity; from a benign condition of hepatic steatosis to a potentially deadly one resulting in cirrhosis and hepatocellular carcinoma. It is currently known that NAFLD is strongly associated with various aspects of metabolic syndrome: insulin resistance, elevated triglyceride levels, obesity, and type two diabetes mellitus. The...
Show moreNon-alcoholic fatty liver disease (NAFLD) is a liver disorder linked to obesity that is rapidly increasing in incidence worldwide. It is a disorder that ranges in severity; from a benign condition of hepatic steatosis to a potentially deadly one resulting in cirrhosis and hepatocellular carcinoma. It is currently known that NAFLD is strongly associated with various aspects of metabolic syndrome: insulin resistance, elevated triglyceride levels, obesity, and type two diabetes mellitus. The multifactorial pathogenesis of NAFLD is still uncertain and closer attention is needed on the effect of one's diet on NAFLD. In this study, we directly compare a westernized diet containing high levels of fat and fructose to a diet high in fat and containing cholate using mouse models in order to determine the role of each dietary factor in the incidence and severity of the different stages of NAFLD. We will evaluate the severity of hepatic steatosis and hepatocellular damage via hematoxylin and eosin (H&E) stained liver tissue and the severity of hepatic fibrosis via trichrome-stained liver tissue. Our hypothesis is that mice on the fructose-based diet are expected to have higher levels of hepatic steatosis and hepatocellular damage relative to mice on the cholate-based diet while mice on the cholate-based diet are expected to have higher levels of hepatic fibrosis relative to the fructose-based diet. The results of this study will aid in elucidating and strengthening the connection between one's diet and the prevalence and severity of NAFLD.
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Date Issued
2018
Identifier
CFH2000340, ucf:45913
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000340
MICROENVIRONMENT CHANGES IN THE PANCREATIC STROMA INDUCED BY INFLAMMATION
Title
MICROENVIRONMENT CHANGES IN THE PANCREATIC STROMA INDUCED BY INFLAMMATION.
Creator
Cline, Kathryn, Altomare, Deborah A., University of Central Florida
Abstract / Description
Pancreatic cancer is the product of microenvironment alterations which emerge from inflammatory signaling and progress to more devastating cases such as Pancreatic Ductal Adenocarcinoma (PDAC). PDAC is extremely aggressive with a statistical five-year survival rate of merely 3%-5%, and is more than relevant to cancer research being that it is the fourth leading cause of cancer-related deaths in the US. Unfortunately pancreatic cancer is often unnoticed until reaching its hardly treatable end...
Show morePancreatic cancer is the product of microenvironment alterations which emerge from inflammatory signaling and progress to more devastating cases such as Pancreatic Ductal Adenocarcinoma (PDAC). PDAC is extremely aggressive with a statistical five-year survival rate of merely 3%-5%, and is more than relevant to cancer research being that it is the fourth leading cause of cancer-related deaths in the US. Unfortunately pancreatic cancer is often unnoticed until reaching its hardly treatable end stages, which perpetuates the low survival rate. The onset of PDAC may be facilitated by the activation of pancreatic stellate cells (PSCs), which secrete collagen and markedly contribute to tissue fibrosis. Inflammatory factors and activation of PSCs are hallmarks of pancreatitis and could increase occurrence rates of pancreatic cancer. The purpose of this thesis is to elucidate inflammatory signaling patterns starting with the onset of acute pancreatitis and through future studies of the more damaging states of chronic pancreatitis and cancer progression. Through the induction of acute pancreatitis in oncogenic and wild type mouse models and evaluating cytokine expression levels via RT-PCR a link between inflammatory signaling and disease state progression will be delineated. This model utilizes mice with mutant KRas, a gene activated in nearly all PDAC incidences, and constitutively active Akt, an oncogene activated in nearly all cancers. Preliminary results indicate that when experimentally inducing pancreatitis in mice predisposed to pancreatic cancer tissue remodeling and leukocyte infiltration is observed as a result of cytokine expression. Furthermore, macrophage and neutrophil stains are positive with one round of cerulein injections proving that acute inflammation is induced by these methods. Pancreatitis is a risk factor for pancreatic cancer which can be caused by environmental factors including smoking, alcohol consumption, and obesity. By understanding the mechanism by which inflammation occurs and the cytokine signaling involved we can attempt inhibit tumor-promoting signaling pathways in the pancreas stroma.
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Date Issued
2016
Identifier
CFH2000104, ucf:45535
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000104