Mechanisms of Beta Cell Proliferation in Mouse and Human Islets

描述(由申请人提供)： 这项提议的目标是为戴维斯博士提供一个全面的5年培训计划，使她能够成为一名独立的学术内分泌学家。通过这个项目，她将在胰岛细胞生物学、活体生理学、遗传学、细胞周期调控、生物信息学、生物统计学和转录调控等领域获得宝贵的研究经验。艾伦·阿蒂博士将担任她事业和科学发展的主要导师。阿蒂博士是糖尿病、遗传学、生物化学、血脂和肥胖症研究领域公认的领导者。他在指导成功的基础科学家方面有着良好的业绩记录。戴维斯博士还组建了一个由杰出的内科科学家组成的指导委员会，提供全方位的职业发展和科学指导。她的指导委员会包括Marc Drezner博士、Molly Carnes博士、Jon Odorico博士和Anath Shalev博士。该研究计划涉及对β细胞增殖的研究，并将利用多种模型来阐明推动这一过程的机制。胰岛β细胞增殖是胰岛素抵抗和肥胖引起的胰岛体积扩大的关键过程。当β细胞质量不足以满足需求时，就会发生高血糖形式的代偿失调。BTBR小鼠在通过引入ob瘦素突变而变得肥胖时会变得严重糖尿病。这种与肥胖相关的2型糖尿病模型已被证明在胰岛细胞增殖方面存在缺陷。中心假说是，未能上调FOXM1或Survivin这两个关键的细胞周期调节因子，会导致细胞增殖减少，最终导致高血糖。这项建议的具体目的包括：1)研究FOXM1在体外和2型糖尿病BTBR-ob模型中促进β细胞增殖的作用；2)确定Survivin是否足以在体外和2型糖尿病BTBR-ob模型中推动β细胞增殖。总而言之，这些目标将使我们能够识别一种新的β细胞增殖途径，该途径可能成为扩大β细胞团的治疗靶点。 与公共健康相关：糖尿病是一种至少每15个美国人中就有一个受到影响的疾病，估计每年至少造成1320亿美元的损失。这项研究旨在了解与肥胖相关的这种疾病发展的基本机制，最终目标是发现新的治疗策略，可能有助于阻止或减缓这种毁灭性疾病的进展。

DESCRIPTION (provided by applicant): The goal of this proposal is to provide Dr. Davis with a comprehensive 5-year training program which will allow her to emerge as an independent academic endocrinologist. Through this program she will gain valuable research experience in the fields of islet cell biology, in vivo physiology, genetics, cell cycle regulation, bioinformatics, biostatistics and transcriptional regulation. Dr. Alan Attie will serve as the primary mentor for her career and scientific development. Dr. Attie is a recognized leader in the fields of diabetes, genetics, biochemistry, lipidology, and obesity research. He has a proven track record of mentoring successful basic scientists. Dr. Davis has also assembled a mentoring committee comprised of outstanding physician scientists to provide the full spectrum of career development and scientific guidance. Her mentoring committee includes Dr. Marc Drezner, Dr. Molly Carnes, Dr. Jon Odorico, and Dr. Anath Shalev. The research plan involves the study of beta cell proliferation and will utilize multiple models to elucidate the mechanisms that drive this process. Beta cell proliferation is a critical process in the expansion of islet mass in response to insulin resistance and obesity. Decompensation in the form of hyperglycemia occurs when the beta cell mass is inadequate to meet demands. The BTBR mouse becomes severely diabetic when made obese by introduction of the ob leptin mutation. This model of obesity-associated type 2 diabetes has been shown to have a defect in islet cell proliferation. The central hypothesis is that failure to upregulate FoxM1 or survivin, two key cell cycle regulators, leads to decreased proliferation and ultimately hyperglycemia. The specific aims of this proposal include 1) Examine the role of FoxM1 in promoting beta cell proliferation in vitro and in the BTBR-ob model of type 2 diabetes; 2) Determine if survivin is sufficient to drive beta cell proliferation in vitro and in the BTBR-ob model of type 2 diabetes. Together, these aims will allow identification of a novel pathway in beta cell proliferation that may serve as a therapeutic target to expand beta cell mass. PUBLIC HEALTH RELEVANCE: Diabetes is a disease that affects at least 1 in 15 Americans and is estimated to cost at least $132 billion annually. This research aims to understand the fundamental mechanisms that underlie the development of this disease in association with obesity with an ultimate goal of uncovering new therapeutic strategies that may help halt or slow progression of this devastating disease.