Inhibition of pancreatic beta cell apoptosis by the transcription factor Slug

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DESCRIPTION (provided by applicant): The applicant is a member of Dr. Joel Habener's laboratory at Massachusetts General Hospital. Dr. Habener has been a leader in the fields of diabetes and endocrinology for over 30 years and has a history of training candidates to be successful independent researchers. Likewise, Massachusetts General Hospital is vibrant and supportive research institution that actively strives to foster the development of academic scientists. My career goal is to complete my training under Dr. Habener's supervision for the next 2-3 years, and then transition to a position as an independent scientist at an academic research and teaching institution. I would benefit from additional training from Dr. Habener so that I may learn methodologies and techniques to manipulate pancreatic endocrine function in vivo to compliment my current in vitro skills. I believe that it is essential that I develop the ability to function effectively in both cell culture and animal models so that I may properly address questions relevant to the management and cure of diabetes mellitus. Loss of beta cell mass through apoptosis is a significant event in the onset and progression of diabetes. Identifying ways to attenuate apoptosis and promote cell survival could provide significant benefit to those afflicted with this disease. I have recently identified the expression of the anti-apoptotic transcription factor Slug in pancreatic beta cells and postulate that Slug may act as a prosurvival factor in the pancreas, similar to its function in progenitor cells in numerous other tissues. To address the role of Slug in the pancreas, I propose to: (1) analyze antiapoptotic function of Slug in cultured pancreatic beta cells, and (2) modulate Slug expression in vivo to protect beta cells from apoptosis. We hope that by further understanding the transcriptional networks which function to regulate beta cell survival, therapeutic strategies can be developed to promote and increase in beta cell mass for the prevention or treatment of diabetes. Over 20 million Americans currently suffer from diabetes mellitus, and that number is predicted to only increase in the foreseeable future. We believe that by understanding the systems regulating beta cell survival, we can develop methods to either prevent cell loss or promote beta cell regeneration. We hypothesize that the pro-survival factor Slug is a regulator of beta cell death, and experimental manipulation of Slug will allow us to maintain or regenerate beta cell mass in order to treat diabetic individuals.