Components of Ras-mediated growth control

描述(由申请人提供)：RAS家族GTP酶是控制细胞增殖、分化和细胞存活的细胞调控系统的关键组成部分。这些系统的不适当调控直接导致人类癌症的发生和发展。这项建议旨在破译RAS家族GTP酶参与的细胞调控网络的组成、组织和功能。我们的重点是分离分子支点，这些支点可以用来转移致癌的RAS诱导的细胞增殖和生存抑制的腐败。我们的具体目标是：1)从机制上阐明TBK1作为致癌RAS相关癌症的肿瘤学靶点；2)通过泛基因组RNAi筛选的矩阵分析捕获致癌RAS合成致死基因；以及3)全面定位人类基因组与EGF受体信号。 公共卫生相关性：人类癌症中致癌RAS信号库的注释进展为确定携带该突变的肿瘤的有效干预措施提供了一个令人兴奋的机会。取得进展的关键瓶颈是难以在致癌RAS调控网络中确定有效的、有针对性的压力点。我们正在应用前沿策略来解码介导致癌RAS转化的关键元素。我们的提议的预期结果和影响将是分离分子支点，选择性地支持致癌的RAS诱导的调控网络的扰动，这可以被用来削弱肿瘤细胞的增殖和生存。我们有广泛的经验和制度支持来开展这一项目。

DESCRIPTION (provided by applicant): Ras family GTPases are critical components of cell regulatory systems that control proliferation, differentiation, and cell survival. Inappropriate regulation of these systems directly contributes to initiation and progression of human cancer. This proposal is directed at decoding the composition, organization, and function of cell regulatory networks engaged by Ras family GTPases. Our focus is on isolation of molecular fulcrums that can be exploited to deflect oncogenic Ras-induced corruption of cell proliferation and survival restraints. Our specific aims are 1) mechanistic elaboration of TBK1 as an oncology target in oncogenic Ras associated cancers; 2) capture of oncogenic Ras synthetic-lethal loci by matrix analysis of pangenomic RNAi screens; and 3) comprehensive mapping of the human kinome to EGF receptor signaling. PUBLIC HEALTH RELEVANCE: Progress in annotation of the signaling repertoire of oncogenic Ras in human cancer presents an exciting opportunity to identify effective interventions for tumors harboring this mutation. The key bottleneck to progress has been the struggle to identify effective targetable pressure-points within the oncogenic Ras regulatory network. We are applying leading-edge strategies to decode the linchpin elements mediating oncogenic Ras transformation. The expected outcomes and impact of our proposal will be isolation of molecular fulcrums, selectively supporting oncogenic Ras-induced perturbation of regulatory networks, that can be exploited to undercut tumor cell proliferation and survival. We have extensive experience and institutional support to carry out this project.