The role of melatonin signaling in regulation of beta-cell survival and function

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DESCRIPTION (provided by applicant): The current proposal outlines a 5-year career development plan for the applicant to develop into an independent research scientist with a research emphasis on elucidating mechanisms by which disruptions in circadian rhythms increase the risk for development of Type 2 diabetes. The applicant has assembled an advisory committee that will guide the applicant through both research and academic career development process. The committee consists of Dr. Peter Butler (mentor) and authority on islet biology and insulin secretion, Dr. Chris Colwell (co-mentor) and a distinguished investigator in circadian biology/melatonin signaling and Dr. Gene Block who is an authority in the study of biological circadian rhythms. The career development plan will consist of acquiring necessary research and literature background expertise in the area of circadian biology and melatonin signaling through post-graduate courses, literature review with mentors, seminar and national meeting attendance. Furthermore, the applicant will develop his career by presenting his work at internal institution seminars and national meetings as well as through interaction with faculty members and visiting scholars at the Larry Hillblom Islet Research Center. This award will also provide the applicant with the opportunity to continue his research work at the Larry Hillblom Islet Research Center and UCLA school of medicine, which allows the trainee to take advantage of the state of the art equipment and facilities in deferent research cores at the center and will supply the trainee with the necessary skills needed to develop an independent scientific career. The research part of the application was developed with the overall goal of establishing whether the circadian hormone melatonin plays a previously unrecognized role in the regulation of beta cell mass and/or function, and whether disruption in beta-cell melatonin signaling pathway might increase risk for Type 2 diabetes. Specifically, Specific Aim 1 will test whether melatonin attenuates beta-cell apoptosis in islets burdened by molecular stress that mimics that in Type 2 diabetes. Specific Aim 2 will test the postulate that melatonin enhances beta-cell function by sensitizing the activation of the cAMP-PKA-EPAC1 pathway in healthy human islets and has the potential to reverse deleterious affects of Type 2 diabetes on insulin secretion. Finally, given the apparent beneficial actions of melatonin on preservation of beta cells against apoptosis and enhanced beta cell function, Specific aim 3 will test the hypothesis that melatonin therapy may delay the progressive decline in beta cell mass and function that are characteristic of Type 2 diabetes. These studies will be first to comprehensively test mechanisms of action by which activation of beta-cell melatonin signaling regulates beta-cell survival and beta-cell function in health and Type 2 diabetes. PUBLIC HEALTH RELEVANCE: There are more than 50 million people in the USA - nearly 20% of the population - with Type 2 diabetes or its precursor impaired fasting glucose. This common disease compromises both quality and length of life, and places a substantial burden on the health care system. Studies outlined in the current proposal will provide insights into pathophysiology of Type 2 diabetes and will examine potential approaches towards prevention and treatment of the disease.