Signal Transduction Leading to Insulin Synthesis

描述（由申请人提供）： 所附的建议书概述了动态培训和系统的研究计划博士基因韦伯为K01资金。Webb博士计划在β细胞信号转导及其对胰岛素合成刺激的影响方面进行综合强化培训。拟议中的工作和独特的培训环境在芝加哥大学将允许韦伯博士实现他的长期目标，在糖尿病领域的一个完全独立的研究生涯。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，以规划进展情况并进行监督。此外，课程工作，校园研讨会和出席国家会议是韦伯博士的计划的组成部分。此外，韦伯博士在芝加哥大学的NIH糖尿病研究和培训中心（DRTC）的参与将增加他的研究和职业发展。该提案的研究部分测试了β细胞的代谢刺激诱导特异性信号转导途径的假设，这些信号转导途径差异调节胰岛素原的翻译。这些机制可能有助于2型糖尿病的发展。在具体目标1中，将进行系统的研究计划，以确定β细胞中葡萄糖刺激的信号转导成分，这些成分也影响细胞产生胰岛素的能力。这将包括通过mTOR途径的信号传导、p38 MAP激酶途径的激活和β细胞上的胰岛素信号传导。因为每个途径调节多个下游激酶，这些也将进行研究。将比较每种途径对胰岛素原合成的影响与微管蛋白合成的影响，以确定对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细胞中蛋白质翻译因子的信号传导的功能后果。这将首先着眼于翻译起始，这是先前显示在胰岛素原翻译中至关重要的步骤。同样，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组分，以获得代谢信号传导的全面视图。

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.