Urocortin III: Regulation and Function in the Islet

描述(由申请人提供)： 葡萄糖是所有哺乳动物细胞的主要能量来源。在正常动物中，血糖水平维持在非常窄的范围内。由胰岛产生的激素，包括胰岛素和胰升糖素，在维持血糖动态平衡方面起着关键作用。最近，促肾上腺皮质激素释放因子(CRF)多肽家族的成员Urocortin(UCN)III被发现在胰岛的细胞中表达。该项目将研究内源性UCN III在胰岛激素分泌中的功能和机制，以及它在调节血糖稳态中的作用。体外原代胰岛培养将用于评估内源性UCN IN对胰岛素和胰升糖素分泌的作用。将产生UCN III缺失或过表达的转基因小鼠，以检测UCN III调节血糖动态平衡的功能。此外，还将研究营养物质和胰岛激素对UCN III在胰腺中表达的影响，以证实胰腺UCN III参与调节血糖稳态的假说。这一拟议项目的结果将为UCN III在糖尿病等代谢紊乱中的可能作用提供重要的见解。这些信息也可能被用于糖尿病的药物设计和治疗应用。职业目标：应聘者的长期职业目标包括在一家领先的研究和教学机构获得教职，从事与激素相关的研究。申请者接受了他的博士学位和最初的关于神经内分泌调节和新陈代谢的博士后培训。候选人将从拟议的项目中获得的培训包括(1)全面了解胰岛激素的调节和功能以及血糖稳态的整体调节，(2)建立体外原代培养以解决特定问题的能力，以及(3)以时间和空间方式产生目的基因缺失或过度表达的转基因小鼠的能力，以研究基因编码产物的功能。从申请中获得的额外知识和研究技能，加上以前的背景，将使申请者能够研究复杂的、多方面的代谢疾病，如糖尿病

DESCRIPTION (provided by applicant): Glucose is a major energy source for all mammalian cells. In normal animals, blood glucose levels are maintained within a very narrow range. Hormones produced by pancreatic islets including insulin and glucagon play a key role in maintaining blood glucose homeostasis. Recently, urocortin (Ucn) III, a member of the corticotropin releasing factor (CRF) peptide family, was found to be expressed in ( cells in the islet. The proposed project will investigate the function and mechanism of endogenous Ucn III in islet hormone secretion and its role in the regulation of glucose homeostasis. In vitro primary islet cultures will be used to assess the role of endogenous Ucn IN on insulin and glucagon secretion. Transgenic mice with either ( cell Ucn III deletion or overexpression will be generated to examine the function of Ucn III in regulating blood glucose homeostasis. In addition, the role of nutrients and islet hormones on the expression of Ucn III in the pancreas will be examined to substantiate the hypothesis that pancreatic Ucn III in involved in the regulation of glucose homeostasis. Results from this proposed project will provide important insight about the possible role of Ucn III in metabolic disorders such as diabetes. The information may also potentially be used for drug design and therapeutic applications for diabetes. Career Goals: The candidate's long-term career objectives include obtaining a faculty position in a leading research and teaching institution to conduct hormone related research. The applicant received his PhD and initial postdoctoral training on neuroendocrine regulation of feeding and metabolism. The training that the candidate will obtain form the proposed project includes (1) a comprehensive understanding of regulation and function of islet hormones and overall regulation of blood glucose homeostasis, (2) the ability to set up in vitro primary cultures to address specific questions and (3) the ability to generate transgenic mice with either deletion or overexpression of gene of interest in a temporal and spatial manner to investigate the function of the gene encoded product. The additional knowledge and research skills acquired from the application, together with previous background, will enable the applicant to study complicated, multifaceted metabolic disorders such as diabetes mellitus