Mechanisms of Beta Cell Proliferation in Mouse and Human Islets

小鼠和人类胰岛β细胞增殖的机制

• 批准号: 7778936
• 负责人: Dawn B Davis
• 金额: $ 14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778936
• 关键词: Adenoviruses; Affect; American; Animals; Apoptosis; Apoptosis Inhibitor; Autoimmune Process; BTBR Mouse; Beta Cell; Biochemistry; Bioinformatics; Biometry; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cellular biology; Defect; Development; Diabetes Mellitus; Disease; Endocrinologist; Face; Failure; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Human; Hyperglycemia; In Vitro; Inflammatory Response; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Islet Cell; Knowledge; Leptin; Measures; Mentors; Messenger RNA; Mitotic; Modeling; Mollies; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathway interactions; Patients; Peripheral; Phenotype; Physicians; Physiological; Physiology; Play; Prediabetes syndrome; Principal Investigator; Process; Proliferating; Regulation; Research; Role; Scientist; Therapeutic; Time; Tissues; Training Programs; Transcription Coactivator; Transcriptional Regulation; Transgenic Mice; Transplantation; United States; Work; career; career development; cdc Genes; cost; diabetes mellitus genetics; diabetic; experience; in vitro Model; in vivo; islet; meetings; metabolic abnormality assessment; novel; novel therapeutics; overexpression; prevent; programs; protein expression; public health relevance; response; survivin; therapeutic target; type I and type II diabetes

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.

描述（由申请人提供）： 该提案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。通过该计划，她将在胰岛细胞生物学，体内生理学，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·阿蒂博士将担任她的职业生涯和科学发展的主要导师。Attie博士是糖尿病、遗传学、生物化学、脂质学和肥胖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记录。戴维斯博士还组建了一个由杰出的医生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β细胞增殖的研究，并将利用多种模型来阐明驱动这一过程的机制。β细胞增殖是响应胰岛素抵抗和肥胖的胰岛质量扩张的关键过程。当β细胞量不足以满足需求时，就会发生高血糖症形式的代偿失调。当通过引入ob瘦素突变使BTBR小鼠肥胖时，BTBR小鼠变得严重糖尿病。这种肥胖相关的2型糖尿病模型已被证明在胰岛细胞增殖方面存在缺陷。核心假设是，未能上调FoxM 1或生存素，两个关键的细胞周期调节因子，导致增殖减少，最终导致高血糖症。该提案的具体目的包括1）检查FoxM 1在体外和2型糖尿病的BTBR-ob模型中促进β细胞增殖的作用; 2）确定生存素是否足以在体外和2型糖尿病的BTBR-ob模型中驱动β细胞增殖。总之，这些目标将允许鉴定β细胞增殖中的新途径，其可以作为扩大β细胞群的治疗靶点。 糖尿病是一种影响至少1/15美国人的疾病，估计每年花费至少1320亿美元。这项研究旨在了解这种疾病发展与肥胖相关的基本机制，最终目标是发现可能有助于阻止或减缓这种毁灭性疾病进展的新治疗策略。