PI-3-Kinase Signaling over Physiologic Time-Scales/Response to Insulin or IGF-1

描述(由申请人提供)： 如果获奖，这笔R03奖助金将在申请者K08奖的最后两年提供补充资金。追加的资金将提供关键资源，如技术援助，这将增强申请人争取进一步赠款支助的能力，并将有助于建立独立研究人员的地位。 2型糖尿病影响了1800万美国人，严重影响了他们的生活质量和寿命。2型糖尿病主要是由胰岛素引起的信号传导受损引起的。胰岛素或高度相关的生长因子IGF-1在激素处理的前10到15分钟内激活的信号通路已被广泛研究。令人惊讶的是，对于更长时间、更具生理相关性的膜-近端信号事件或对胰岛素水平下降的反应，人们知之甚少。这项拨款申请建议使用我们在相关K08奖资助的研究期间开发的强大成像技术来研究关键的PI-3-激酶途径在长时间过程中的行为，以响应胰岛素或IGF-1水平的上升或下降。我们还提出了一种筛选方法来确定Ptdlns(3，4，5)P3作为胰岛素/IGF-1信号通路中潜在的新元件的新靶点。我们预计，对胰岛素信号通路的更好理解将最终导致改善胰岛素抵抗和II型糖尿病的治疗策略。

DESCRIPTION (provided by applicant): If awarded, this R03 grant would provide supplemental funding during the final two years of the applicant's K08 award. The additional funding would provide crucial resources, such as technical assistance, that would enhance the applicant's ability to compete for further grant support and would facilitate establishment as an independent researcher. Type 2 diabetes mellitus affects 18 million Americans, seriously impacting on their quality of life and longevity. Type 2 diabetes mellitus is caused primarily by impaired signaling by insulin. The signaling pathways that are activated within the first ten to fifteen minutes of hormone treatment by insulin or the highly related growth factor IGF-1 have been studied extensively. Surprisingly little is known about membrane-proximal signaling events over longer, more physiologically relevant, time-courses or in response to falling insulin levels. This grant application proposes to study the behavior of the crucial PI-3-kinase pathway over long time-courses in response to rising or falling insulin or IGF-1 levels using powerful imaging techniques that we developed during our research funded by the associated K08 award to track the PI-3-kinase pathway. We also propose a screen to identify novel targets of Ptdlns(3,4,5)P3 as potentially novel elements in the insulin/IGF-1 signaling pathway. We expect that improved understanding of the insulin signaling pathway will eventually lead to improved treatment strategies for insulin resistance and type II diabetes mellitus.