Signal Transduction Leading to Insulin Synthesis

导致胰岛素合成的信号转导

• 批准号: 6722540
• 负责人: GENE C WEBB
• 金额: $ 10.56万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722540
• 关键词: autocrine; biological signal transduction; enzyme activity; enzyme induction /repression; glucose; hormone biosynthesis; immunoprecipitation; insulin; laboratory mouse; microarray technology; mitogen activated protein kinase; molecular cloning; northern blottings; pancreatic islet function; phosphorylation; proinsulin; radioimmunoassay; translation factor

DESCRIPTION (provided by applicant): The enclosed proposal outlines the dynamic training and systematic research plans for Dr. Gene Webb for K01 funding. Dr. Webb plans an integrated and intensive training program in the area of beta-cell signal transduction and its impact on stimulation of insulin synthesis. The proposed work and unique training environment at The University of Chicago will allow Dr. Webb to achieve his long-term goal of a fully independent research career in the field of diabetes. Training and development will entail intensive mentoring by Dr. Fredric Wondisford and Dr. Donald Steiner, including weekly meetings, review of manuscripts and grants, as well as a biannual meeting by an advisory committee to chart progress and provide oversight. Additionally, course work, campus seminars and attendance at national meetings are integral components of Dr. Webb's program. Further, Dr. Webb's participation in The University of Chicago's NIH Diabetes Research and Training Center (DRTC) will augment both his research and career development. The research component of the proposal tests the hypothesis that metabolic stimulation of beta cells induces specific signal-transduction pathways that differentially regulate the translation of proinsulin. These mechanisms may contribute to the development of type 2 diabetes. In Specific Aim 1, a systematic research plan will be undertaken to define signal transduction components that are glucose-stimulated in beta cells and that also impact the ability of the cell to produce insulin. This will include signaling through the mTOR pathway, activation of the p38 MAP kinase pathway, and insulin signaling on the beta cell. Because each pathway regulates multiple downstream kinases, these will be investigated also. The impact on proinsulin synthesis will be compared to tubulin synthesis for each pathway to determine effects specific to proinsulin synthesis. In Specific Aim 2, the functional consequence of signaling through these pathways on protein translation factors in the beta cell is studied. This will look first at translation initiation, a step previously shown to be crucial in proinsulin translation. Again, effects specific to proinsulin will be determined. Specific Aim 3 utilizes microarray techniques to identify and characterize glucose-responsive signal transduction components in the beta cell to gain a comprehensive view of metabolic signaling.

描述（由申请人提供）： 随附的提案概述了 Gene Webb 博士获得 K01 资助的动态培训和系统研究计划。韦伯博士计划在 β 细胞信号转导及其对刺激胰岛素合成的影响领域开展综合强化培训计划。芝加哥大学拟议的工作和独特的培训环境将使韦伯博士实现他在糖尿病领域完全独立的研究生涯的长期目标。培训和发展将需要 Fredric Wondisford 博士和 Donald Steiner 博士的密集指导，包括每周会议、手稿和拨款审查，以及咨询委员会每年两次的会议，以绘制进展情况并提供监督。此外，课程作业、校园研讨会和参加全国会议也是韦伯博士课程的组成部分。此外，Webb 博士参与芝加哥大学 NIH 糖尿病研究和培训中心 (DRTC) 将增强他的研究和职业发展。该提案的研究部分测试了以下假设：β 细胞的代谢刺激会诱导特定的信号转导途径，从而差异调节胰岛素原的翻译。这些机制可能导致 2 型糖尿病的发生。在具体目标 1 中，将开展一项系统研究计划，以确定在 β 细胞中受葡萄糖刺激并影响细胞产生胰岛素的能力的信号转导成分。这将包括通过 mTOR 通路的信号传导、p38 MAP 激酶通路的激活以及 β 细胞上的胰岛素信号传导。由于每条途径调节多个下游激酶，因此也将对这些激酶进行研究。对胰岛素原合成的影响将与每个途径的微管蛋白合成进行比较，以确定胰岛素原合成的特异性效果。在具体目标 2 中，研究了通过这些途径对 β 细胞中蛋白质翻译因子进行信号传导的功能结果。这将首先关注翻译起始，这是先前证明在胰岛素原翻译中至关重要的步骤。再次，将确定胰岛素原的特异性作用。具体目标 3 利用微阵列技术来识别和表征 β 细胞中的葡萄糖响应信号转导成分，以获得代谢信号传导的全面视图。