Signal Transduction Leading to Insulin Synthesis

导致胰岛素合成的信号转导

• 批准号: 6993574
• 负责人: GENE C WEBB
• 金额: $ 11.15万
• 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/6993574
• 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)： 所附提案概述了吉恩·韦伯博士在K01基金方面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方面开展一项综合的强化培训计划。芝加哥大学拟议的工作和独特的培训环境将使韦布博士能够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、审查手稿和赠款，以及咨询委员会一年两次的会议，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都是韦布博士课程不可或缺的组成部分。此外，韦伯博士参加芝加哥大学国立卫生研究院糖尿病研究和培训中心(DRTC)将加强他的研究和职业发展。该提案的研究部分测试了这样一种假设，即对β细胞的新陈代谢刺激会诱导特定的信号转导途径，从而不同地调节胰岛素原的翻译。这些机制可能参与了2型糖尿病的发生发展。在具体目标1中，将进行系统的研究计划，以确定在β细胞中葡萄糖刺激的信号转导成分，以及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，激活p38 MAP激酶通路，以及在β细胞上的胰岛素信号。因为每条通路都调节多个下游的激酶，所以这些也将被研究。对胰岛素原合成的影响将与每条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影响。在具体目标2中，研究了通过这些途径对β细胞中的蛋白质翻译因子进行信号传递的功能后果。这将首先关注翻译的启动，这一步骤以前被证明在胰岛素原翻译中是至关重要的。同样，胰岛素原的特定影响将被确定。特殊目的3利用微阵列技术来识别和表征β细胞中的葡萄糖反应信号转导成分，以获得代谢信号的全面看法。