UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

My laboratory uses cell, molecular, and developmental biology tools to decipher the mechanisms that underlie normal mammalian pancreas formation and pancreatic diseases, including diabetes and pancreatic cancer. In particular, we are focusing on the role of embryonic signaling pathways, including Hedgehog and Wnt signaling, during pancreas formation and function. We are using state-of-the-art tools, including transgenic mice and small chemical compounds, to manipulate the activity of these pathways during pancreas formation and in mature tissue. The goal of these studies is to determine whether controlled activation and de-activation of embryonic signaling pathways permits ( a) the initiation of the formation of insulin-producing ß-cells from uncommitted stem cells, (e.g., embryonic and adult stem cells), and ( b) prevention of the formation and growth of pancreatic tumors.

Pancreas development: We employ knockout and transgenic mouse lines to study the effects of known signaling pathways involved in cell proliferation, differentiation, and migration on pancreas morphogenesis and function. In particular, we are interested in understanding how components of the Hedgehog and Wnt signaling pathways influence endocrine cell differentiation and maintenance of organ properties in adult organisms. Our previous studies have shown that ectopic activation of Hedgehog signaling in pancreatic tissue blocks organ formation. Using the Cre-loxP technology, we are currently eliminating Hedgehog signaling from pancreatic epithelium to determine whether low-level Hedgehog signaling is required for some aspects of pancreas formation and islet function. In addition, using the same Cre-loxP technology, we are exploring the interactions between Hedgehog and Wnt signaling, another pathway known to regulate cell differentiation in other organs. Preliminary results indicate synergistic activities of these pathways. We are currently exploring these interactions in detail and anticipate that these studies will provide important information to optimize differentiation protocols to generate insulin-producing cells from progenitor cells.

Diabetes and regeneration of ß-cells: In collaboration with Dr. Gerard Evan, we have started to analyze ß-cell regeneration in pIns-cMycER TAM transgenic mice that express cMyc , a transcription factor known to cause apoptosis, in insulin-producing ß-cells. Upon transgene activation with tamoxifen, ß-cells die, and transgenic mice become hyperglycemic. Interestingly, insulin-producing cells reappear within days after termination of tamoxifen treatment, and mice eventually regain normoglycemia. Thus, these insulin promoter-cMyc transgenic mice present a novel model system to study ß-cell regeneration in mice. A detailed understanding of the underlying molecular mechanisms may allow us to devise strategies to increase ß-cell mass and the number of available islets for transplantation in diabetic patients.

Model systems for pancreatic cancer: Overt hedgehog signaling has been implicated in cancer formation in various tissues, however, it had not previously been linked to the formation of pancreatic adenocarcinomas, an aggressive form of cancer that is virtually incurable. In collaboration with Martin McMahon's laboratory at the UCSF Cancer Center, we have demonstrated that deregulated Hedgehog signaling can promote proliferation of pancreatic cancer cell lines and that inhibition of Hedgehog signaling blocks cell proliferation. Currently, we are generating transgenic animals that ectopically express Hedgehog signaling molecules in pancreatic tissue to address their tumorigenic activity in vivo . Furthermore, our work describes interactions between Hedgehog and Wnt signaling in pancreatic adenocarcinoma. Using small chemical compounds, we were able to demonstrate that simultaneous inhibition of both pathways has a more pronounced effect on killing pancreatic cancer cells. These studies may allow us to devise more effective methods to combat this deadly disease.

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