The Role of Glucocorticoids in Development and Function of the Endocrine Pancreas

描述(由申请人提供)：本提案概述了候选人Ronadip R.Banerjee，M.D.，Ph.D.的五年综合培训计划，以帮助他作为一名内科科学家发展成为一名独立的研究员。Banerjee博士的研究计划，调查糖皮质激素在胰腺内分泌发育和功能中的作用，将在斯坦福大学发育生物学教授兼霍华德·休斯研究员Seung Kim博士的实验室进行。该研究计划探索一种假设，即糖皮质激素通过抑制生长、抑制激素分泌和基因表达来调节内分泌胰腺的发育和功能。这一假说有三个特定的目的：(1)确定GCs在内分泌胰腺发育和出生后扩张中的作用；(2)阐明出生后和成年期胰岛GC信号失活的代谢后果；(3)利用糖皮质激素过量的环境和药理学模型，评估取消胰岛GC信号对代谢应激反应的影响。为了实现这些目标，该项目使用“Cre-Lox”系统在老鼠身上产生条件性的“基因敲除”遗传模型。代谢表型分析，结合专门的细胞和分子分析，将在分子水平上确定特定细胞类型的GR条件性缺失的生理后果。这些目标的实现应该确定糖皮质激素如何直接调节胰岛的生长和功能。此外，该项目应该提供对糖皮质激素诱导的糖尿病的分子基础的洞察，并识别可能在糖尿病治疗中提出新的治疗靶点的特定分子缺陷。同时，Banerjee博士将完成由咨询委员会监督的有组织的职业发展培训，咨询委员会由斯坦福大学内分泌学和新陈代谢部门的领先内科科学家和导师组成。这些将包括教学、临床、教学和管理经验，以实现他的长期目标，即成为一名全面发展的内科科学家，有能力在领先的学术医学中心管理研究实验室。 与公共卫生相关：糖尿病目前在美国困扰着多达2500万人，是导致死亡和发病率的主要原因，包括失明、心脏病、中风和肾脏疾病。显然，这是一个重大的公共卫生问题。糖尿病的主要缺陷之一是胰腺无法产生足够的胰岛素来匹配升高的血糖水平。我们的建议是研究“应激”荷尔蒙，即糖皮质激素，如何直接破坏胰腺分泌荷尔蒙细胞的正常生长和功能。了解这一过程可能导致专门针对胰腺功能障碍的新疗法，胰腺功能障碍是糖尿病疾病过程的基石。

DESCRIPTION (provided by applicant): This proposal outlines an integrative five year training program for the candidate, Ronadip R. Banerjee, M.D., Ph.D., in his development as a physician-scientist towards becoming an independent investigator. Dr. Banerjee's research proposal, investigating the role of glucocorticoids in the development and function of the endocrine pancreas, will be carried out in the laboratory of Dr. Seung Kim, Professor of Developmental Biology and Howard Hughes Investigator at Stanford University. The research plan explores the hypothesis that glucocorticoids regulate the development and function of the endocrine pancreas by inhibiting growth, and suppressing hormone secretion and gene expression. This hypothesis is evaluated by three Specific Aims: (1) to determine the role of GCs in the development and postnatal expansion of the endocrine pancreas, (2) to elucidate the metabolic consequences of inactivating GC signaling in islets in postnatal and adult periods, and (3) to evaluate the consequences of abolishing GC signaling in islets to the metabolic stress response by using environmental and pharmacologic models of glucocorticoid excess. To accomplish these Aims, the project uses the "Cre-Lox" system to generate conditional "knockout" genetic models in mice. Metabolic phenotyping, in conjunction with specialized cell and molecular analyses will ascertain the physiologic consequences of the cell-type-specific conditional deletion of GR at a molecular level. Accomplishment of these Aims should identify how glucocorticoids directly regulate islet growth and function. Additionally, this project should provide insight into the molecular underpinnings of glucocorticoid-induced diabetes, and identify specific molecular defects that may present novel therapeutic targets in diabetes treatment. Concurrently, Dr. Banerjee will complete structured career development training supervised by an Advisory Committee comprised of leading physician-scientists and mentors within the Stanford Endocrinology and Metabolism division. These will include didactic, clinical, teaching, and managerial experience necessary to achieve his long-term goal of becoming a well-rounded physician-scientist capable of running a research laboratory at a leading academic medical center. PUBLIC HEALTH RELEVANCE: Diabetes, which afflicts as many as 25 million people in the United States today, is a leading cause of death, and morbidity, including blindness, heart disease, stroke, and kidney disease. Clearly, it is a major public health problem. One of the major defects in diabetes is the failure of the pancreas to produce enough insulin to match the increased blood glucose levels. Our proposal investigates how "stress" hormones, called glucocorticoids, might directly disrupt the normal growth and function of the hormone-producing cells of the pancreas. Understanding this process may lead to new therapies directed specifically at the pancreas dysfunction that is a cornerstone of the diabetic disease process.