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

褪黑激素信号传导在调节 β 细胞存活和功能中的作用

• 批准号: 8110457
• 负责人: ALEKSEY V MATVEYENKO
• 金额: $ 14.33万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-10 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110457
• 关键词: Address; Advisory Committees; Affect; Apoptosis; Apoptotic; Area; Attenuated; Award; Beta Cell; Biological; Biological Preservation; Biology; CREB1 gene; Cardiovascular Physiology; Cell Survival; Cell physiology; Characteristics; Circadian Rhythms; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Darkness; Development; Development Plans; Diabetes Mellitus; Diet; Disease; Equipment; Exercise; Faculty; Failure; Fatty acid glycerol esters; Functional disorder; Genes; Glucose; Goals; Health; Healthcare Systems; Hormones; Human; Humoral Immunities; Hyperglycemia; Impaired fasting glycaemia; In Vitro; Incidence; Individual; Institution; Insulin; Insulin Resistance; Link; Literature; Longevity; Mediating; Melatonin; Melatonin Receptors; Mentors; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Pathway interactions; Pattern; Physiologic pulse; Physiological; Pilot Projects; Pineal gland; Play; Population; Prevention; Process; Public Health; Rattus; Receptor Signaling; Receptor, Melatonin, MT2; Regulation; Research; Research Personnel; Retina; Review Literature; Risk; Role; Scientist; Signal Pathway; Signal Transduction; Sleep; Stimulus; Stress; Structure of beta Cell of islet; Testing; Visit; Work; authority; career; career development; genome wide association study; glucose metabolism; insight; insulin secretion; islet; lifestyle factors; medical schools; meetings; member; noradrenergic; prevent; public health relevance; receptor; response; shift work; skills

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.

描述（由申请人提供）：目前的提案概述了申请人发展成为独立研究科学家的5年职业发展计划，其研究重点是阐明昼夜节律中断增加2型糖尿病发展风险的机制。申请人已经组建了一个咨询委员会，该委员会将指导申请人完成研究和学术职业发展过程。该委员会由Peter Butler博士（导师）和胰岛生物学和胰岛素分泌方面的权威、Chris科尔韦尔博士（共同导师）和昼夜节律生物学/褪黑激素信号传导方面的杰出研究者以及生物昼夜节律研究方面的权威Gene Block博士组成。 职业发展计划将包括通过研究生课程、与导师一起进行文献综述、参加研讨会和国家会议，在昼夜节律生物学和褪黑激素信号传导领域获得必要的研究和文献背景专业知识。此外，申请人将通过在内部机构研讨会和国家会议上展示自己的工作，以及通过与拉里·希尔布卢姆岛研究中心的教职员工和访问学者的互动来发展自己的职业生涯。该奖项还将为申请人提供继续在Larry Hillblom Islet研究中心和加州大学洛杉矶分校医学院进行研究工作的机会，这使受训者能够利用该中心不同研究核心的最先进设备和设施，并为受训者提供发展独立科学事业所需的必要技能。 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β细胞质量和/或功能的调节中起着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可能增加2型糖尿病的风险。具体来说，具体目标1将测试褪黑激素是否减弱胰岛中的β细胞凋亡，胰岛承受模拟2型糖尿病的分子应激。具体目标2将测试以下假设：褪黑激素通过敏化健康人胰岛中cAMP-PKA-EPAC 1通路的激活来增强β细胞功能，并且具有逆转2型糖尿病对胰岛素分泌的有害影响的潜力。最后，鉴于褪黑激素对保护β细胞抗凋亡和增强β细胞功能的明显有益作用，具体目标3将检验褪黑激素治疗可以延迟β细胞质量和功能的进行性下降的假设，这是2型糖尿病的特征。这些研究将首次全面测试β细胞褪黑激素信号传导的激活调节健康和2型糖尿病中β细胞存活和β细胞功能的作用机制。 公共卫生关系：美国有超过5000万人-近20%的人口-患有2型糖尿病或其前驱空腹血糖受损。这种常见疾病损害了生命的质量和长度，并给卫生保健系统带来了沉重的负担。目前提案中概述的研究将为2型糖尿病的病理生理学提供见解，并将研究预防和治疗该疾病的潜在方法。