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

描述(由申请人提供)：目前的提案概述了申请人发展为独立研究科学家的5年职业发展计划，研究重点是阐明昼夜节律紊乱增加2型糖尿病发展风险的机制。申请者已经组建了一个咨询委员会，该委员会将指导申请者完成研究和学术职业发展过程。该委员会由皮特·巴特勒博士(导师)和胰岛生物学和胰岛素分泌方面的权威人士组成，克里斯·科尔韦尔博士(共同导师)和昼夜节律/褪黑激素信号方面的杰出研究员克里斯·科尔韦尔博士以及研究生物昼夜节律的权威吉恩·布洛克博士组成。 职业发展计划将包括通过研究生课程、与导师一起审查文献、研讨会和出席全国会议，获得昼夜节律生物学和褪黑激素信号领域的必要研究和文学背景专门知识。此外，申请者将通过在内部机构研讨会和全国会议上展示他的工作，以及通过与拉里·希尔布洛姆岛研究中心的教职员工和访问学者的互动来发展他的职业生涯。该奖项还将为申请者提供在拉里·希尔布洛姆岛研究中心和加州大学洛杉矶分校医学院继续他的研究工作的机会，这使得受训人员能够利用该中心不同研究中心的最先进的设备和设施，并将为受训人员提供发展独立科学生涯所需的必要技能。 开发该应用程序的研究部分的总体目标是确定昼夜节律激素褪黑激素是否在调节β细胞质量和/或功能方面发挥以前未被认识到的作用，以及β细胞褪黑激素信号通路的中断是否会增加患2型糖尿病的风险。具体地说，专门的目标1将测试褪黑素是否能减轻胰岛中的β细胞凋亡，这些胰岛承受着与2型糖尿病相似的分子压力。特定目标2将测试褪黑素通过敏化健康人胰岛中cAMP-PKA-EPAC1途径的激活来增强β细胞功能的假设，并具有逆转2型糖尿病对胰岛素分泌的有害影响的潜力。最后，鉴于褪黑素在保护贝塔细胞免受凋亡和增强贝塔细胞功能方面明显的有益作用，特定目标3将测试褪黑素疗法可能延缓2型糖尿病特征的贝塔细胞质量和功能进行性下降的假设。这些研究将首次全面测试在健康和2型糖尿病中，通过激活β细胞褪黑素信号调节β细胞存活和β细胞功能的作用机制。 与公共卫生相关：美国有5000多万人患有2型糖尿病或其先兆空腹血糖受损，占总人口的近20%。这种常见疾病损害了生命质量和生命长度，给卫生保健系统带来了沉重的负担。当前提案中概述的研究将提供对2型糖尿病的病理生理学的见解，并将审查预防和治疗该疾病的潜在方法。

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.