Positive and Negative Regulation of RTK-Ras Signaling

描述（由申请人提供）：当前授权的广泛目标是阐明控制响应受体酪氨酸激酶（RTK）激活产生的信号的生物学结果的监管原则。RTK触发细胞内信号的中心途径涉及Ras通过其鸟嘌呤核苷酸交换因子Sos的激活。因此，目前资助的一个主要组成部分旨在确定Sos介导的Ras激活的分子和细胞基础。本竞争性修订申请是我们根据NOT-OD-09-058号通知提交的，标题为“NIH宣布恢复法案资金可用于竞争性修订申请”，旨在通过整合我们的合作者纽约大学化学系的Paramjit Arora博士开创的新型化学方法来加强这些努力。总体目标是开发Sos介导的Ras活化的高度特异性小分子调节剂。所使用的策略建立在Arora博士在产生可以稳定保持1-螺旋构象的短肽方面的专业知识基础上。具体而言，我们的实验设计旨在产生短的稳定的人工1-螺旋，其在体外破坏Ras-Sos相互作用并在体内损害RTK介导的Ras活化。鉴于PI和Arora博士的互补专业知识以及有希望的初步数据，在指定时间范围内完成拟定研究的可能性非常高。 公共卫生相关性：信号转导是一个基本的过程，使细胞能够从细胞外环境中获取信息，并适当地响应这些信息。本申请的重点是建立新的方法来靶向特定的信号事件。因此，本文提出的实验应该推进我们对信号转导过程的分子理解，并提供对许多人类疾病背后的信号传导缺陷的见解。

DESCRIPTION (provided by applicant): The broad objective of the current grant is to elucidate the regulatory principles that govern the biological outcome of signals that are generated in response to receptor tyrosine kinase (RTK) activation. A central route by which RTKs trigger intracellular signals involves the activation of Ras by its guanine nucleotide exchange factor Sos. Consequently, a major component of the current grant is aimed at defining the molecular and cellular basis for Sos-mediated Ras activation. This Competitive Revision Application, which we are submitting in response to Notice NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications" seeks to augment these efforts through the integration of a novel chemical approach pioneered by our collaborator, Dr. Paramjit Arora from the Department of Chemistry, New York University. The overall goal is to develop highly specific small molecule modulators of Sos-mediated Ras activation. The strategy to be used builds on the expertise of Dr. Arora in generating short peptides that can stably maintain 1-helical conformation. Specifically, our experimental design is aimed at the generation of short stable artificial 1-helices that disrupt Ras-Sos interaction in vitro and compromise RTK-mediated Ras activation in vivo. Given the complementary expertise of the PI and Dr. Arora and the promising preliminary data, the likelihood that the proposed studies would be brought to completion within the indicated time frame is exceedingly high. PUBLIC HEALTH RELEVANCE: Signal transduction is a fundamental process that enables cells to acquire information from the extracellular environment and respond to this information appropriately. This application focuses on the establishment of new approaches to target specific signaling events. Experiments proposed herein should thus advance our molecular understanding of signal transduction processes and provide insights into signaling defects that underlie a host of human diseases.