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

糖皮质激素在内分泌胰腺发育和功能中的作用

基本信息

批准号：
8249448
负责人：
Ronadip Ralph Banerjee
金额：
$ 15.39万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249448
关键词：
Academic Medical Centers Adrenal Glands Adult Adverse effects Advisory Committees Alpha Cell Anti-Inflammatory Agents Anti-inflammatory Beta Cell Binding Blindness Blood Glucose Cause of Death Cell Proliferation Cells Clinical Defect Development Developmental Biology Diabetes Mellitus Disease Disease Progression Doctor of Medicine Doctor of Philosophy Educational process of instructing Endocrinology Epidemic Failure Feedback Functional disorder Gene Deletion Gene Expression Genetic Models Glucagon Glucocorticoid Receptor Glucocorticoids Goals Growth Heart Diseases Hormones Hypoglycemia Immune In Vitro Insulin Islets of Langerhans Kidney Diseases Knock-out Laboratories Laboratory Research Lead Ligands Link Literature Liver Lung Mentors Metabolic Metabolic Control Metabolic Pathway Metabolic stress Metabolism Modeling Molecular Morbidity - disease rate Mus Nuclear Hormone Receptors Nutrient Pancreas Pathologic Pathway interactions Perinatal Phenotype Physicians Physiological Physiological Processes Play Process Public Health Regulation Regulator Genes Research Research Personnel Research Proposals Role Running Scientist Signal Transduction Stress Stroke Structure System Thyroid Hormones Tissues Training Training Programs United States Universities biological adaptation to stress carbohydrate metabolism career development cell type diabetic experience glucose metabolism in vivo insight islet lipid metabolism mortality mouse model new therapeutic target postnatal professor public health relevance response steroid hormone

项目摘要

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.

描述（由申请人提供）：本提案概述了候选人 Ronadip R. Banerjee 医学博士、哲学博士的五年综合培训计划，帮助他从一名医师兼科学家发展成为一名独立研究者。 Banerjee 博士的研究计划旨在调查糖皮质激素在内分泌胰腺发育和功能中的作用，该研究计划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 博士的实验室中进行。该研究计划探讨了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的假设。该假设通过三个具体目标进行评估：(1) 确定 GC 在内分泌胰腺的发育和出生后扩张中的作用，(2) 阐明出生后和成年期胰岛中 GC 信号失活的代谢后果，以及(3) 通过使用糖皮质激素过量的环境和药理学模型来评估消除胰岛中的GC信号传导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”系统在小鼠中生成条件“敲除”遗传模型。代谢表型分析与专门的细胞和分子分析相结合，将在分子水平上确定细胞类型特异性条件性 GR 缺失的生理后果。实现这些目标应确定糖皮质激素如何直接调节胰岛生长和功能。此外，该项目应深入了解糖皮质激素诱发的糖尿病的分子基础，并确定可能为糖尿病治疗提供新治疗靶点的特定分子缺陷。同时，班纳吉博士将完成由斯坦福大学内分泌和代谢部门内顶尖医师科学家和导师组成的咨询委员会监督的结构化职业发展培训。这些将包括实现他的长期目标所必需的教学、临床、教学和管理经验，即成为一名能够在领先的学术医疗中心运营研究实验室的全面的医师科学家。公共健康相关性：如今，糖尿病困扰着美国多达 2500 万人，是导致失明、心脏病、中风和肾病等疾病和死亡的主要原因。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。我们的提案研究了“压力”激素（称为糖皮质激素）如何直接破坏胰腺激素产生细胞的正常生长和功能。了解这一过程可能会带来专门针对胰腺功能障碍的新疗法，而胰腺功能障碍是糖尿病疾病过程的基石。