COBRE PROJ 7: CONTROL OF TUMOR GROWTH BY RAS-RELATED PROTEINS

COBRE 项目 7：通过 RAS 相关蛋白控制肿瘤生长

基本信息

批准号：
8167780
负责人：
Geoffrey J. Clark
金额：
$ 24.2万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8167780
关键词：
Apoptosis Cells Computer Retrieval of Information on Scientific Projects Database Development Family Family member Farnesyl Transferase Inhibitor Funding Grant Growth Growth and Development function HRAS gene Human Institution Investigation Malignant Neoplasms Mediating Mus Oncogene Proteins Process Proteins RALGDS gene RAS Superfamily Proteins Ras Inhibitor Research Research Personnel Resources Series Signal Pathway Source System Tumorigenicity United States National Institutes of Health Work cancer therapy inhibitor/antagonist novel ras Oncogene ras Proteins small molecule tumor growth

Apoptosis Cells Computer Retrieval of Information on Scientific Projects Database Development Family Family member Farnesyl Transferase Inhibitor Funding Grant Growth Growth and Development function HRAS gene Human Institution Investigation Malignant Neoplasms Mediating Mus Oncogene Proteins Process Proteins RALGDS gene RAS Superfamily Proteins Ras Inhibitor Research Research Personnel Resources Series Signal Pathway Source System Tumorigenicity United States National Institutes of Health Work cancer therapy inhibitor/antagonist novel ras Oncogene ras Proteins small molecule tumor growth

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项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Geoffrey Clark, PI Specific Aim 1: Investigation of the RASSF family of Ras effectors in transformation The Ras oncogene has been implicated as a key player in the development of more than a third of human cancers. Ras appears to function by activating multiple, heterologous effector proteins that regulate synergistic signaling pathways controlling growth and development. Experimentally, excess Ras activation leads to vigorous transformation and the best characterized Ras effector proteins are themselves oncoproteins. However, excessive activation of Ras can also cause cells to undergo growth arrest and apoptosis. This suggests that Ras proteins may activate a sub-set of effectors that, rather than promoting transformation, mediate growth inhibition. It would seem reasonable to suppose that such effector systems would have to be subverted during the transformation process to allow progression to tumorigenicity. Specific Aim 2: Development of novel small molecule inhibitors of Ras action Ras has been identified as a prime candidate for targeted anti-cancer therapy for more than two decades, but attempts to develop specific inhibitors of Ras have so far proved ineffective. The best known attempt involved a series of Farnesyl transferase inhibitors that actually do work well on H-Ras but are ineffective against the most important member of the family, K-Ras. Recent work has shown that the most important Ras effector for transformation in human systems is the RalGDS group of effectors. This contrasts with results in murine systems which have implicated Rafs as the key effectors. No inhibitors of RalGDS function have been described.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。杰弗里·克拉克（Geoffrey Clark），pi 特定目的1：在转化中对RASF家族的调查 Ras Oncogene已被牵涉到超过三分之一的人类癌症发展中的关键参与者。 RAS似乎通过激活多种异源效应子蛋白来调节控制生长和发育的协同信号通路。在实验上，过量的RAS激活会导致剧烈的转化，而最佳特征的RAS效应蛋白本身就是癌蛋白。但是，过度激活RA也会导致细胞发生生长停滞和凋亡。这表明RAS蛋白可能会激活效应子的子集，而不是促进转化，而是介导生长抑制。似乎可以合理地假设必须在转化过程中颠覆这种效应系统才能使肿瘤性进展。特定目的2：新型小分子抑制剂的开发RAS作用 RAS已被确定为有针对性抗癌治疗的主要候选者已有二十多年了，但是迄今为止，试图开发RAS的特定抑制剂的尝试被证明是无效的。最著名的尝试涉及一系列Farnesyl转移酶抑制剂，这些抑制剂实际上在H-RAS上确实效果很好，但对家族中最重要的成员K-RAS无效。最近的工作表明，人类系统中最重要的RAS效应器是Ralgds效应子组。这与将RAFS视为关键效应子的鼠系统的结果形成鲜明对比。尚未描述RALGDS功能的抑制剂。