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The pancreas contains two functional compartments that look different under a microscope, the endocrine and exocrine pancreas. The endocrine pancreas is responsible for regulating glucose homeostasis. The primary role of the exocrine pancreas is the production of enzymes for nutrient digestion. The biology of the pancreas has been studied intensively to improve treatment options for devastating pancreatic diseases, such as pancreatitis (pancreatic swelling), a type of cancer called pancreatic ductal adenocarcinoma (PDAC) and diabetes. Pancreatic diseases are affected by environmental factors, like alcohol and smoking. Smoking is an independent risk factor for pancreatic diseases and smoking cessation is the most effective strategy to reduce the risk of pancreatic cancer. While studies on pancreatic diseases increased our understanding of how molecules interact with each other (molecular pathways) and lead to the onset of disease, there are still many questions unanswered. Pancreatic cancer is one of the deadliest human malignancies and is linked to cigarette use. The treatment for severe pancreatitis has not changed in the last decade still focusing on pain control and fluids.
Telomerase is a molecule that has emerged as a critical stem cell factor in the recent years. The main function of the telomerase is to add telomere repeats to chromosome ends, thereby preventing the molecular interactions that should lead to cell death. In serving this function, telomerase is the immortality enzyme that enables immortal growth of pancreatic cancers and other human tumors. However, there is growing evidence that the telomerase reverse transcriptase (TERT) has other functions, such as a role in stem cell function and tissue stability (homeostasis). It is striking that genetic studies have linked alterations in the TERT gene with an increased risk of pancreatic cancer in patients.
Pancreatic cancer remains such an intractable problem in part because our understanding of how the adult pancreas regenerates is very poorly understood. I will study pancreas homeostasis and regeneration in mice that have a fluorescent molecule attached to the TERT gene that can be seen with a fluorescence microscope. This novel approach allows rare cells that have telomerase to be identified and studied functionally as the pancreas naturally repairs itself. In the second part of my proposal I will investigate if TERT expressing cells are the cells that become pancreatic cancer in a mouse model of pancreatic cancer. I will also determine if TERT is required for pancreatic regeneration and pancreatic cancer.
The successful completion of the proposed aims will advance our understanding of pancreatic cancers, and contribute more broadly to the fields of stem cell biology, cancer biology and signal transduction (molecular pathways). Determining the importance of TERT expression in pancreatic diseases and its function in cancer cells is a novel approach to detect and treat pancreatic diseases. Additionally I believe that my studies will reveal key new molecular pathways that regulate cancer cell behavior and may identify novel targeted therapeutic strategies for treatment of cancer. | 