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

• 批准号: 7959808
• 负责人: Geoffrey J. Clark
• 金额: $ 11.74万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959808
• 关键词: Apoptosis; Cells; Centers of Research Excellence; 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; Molecular Target; 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

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 杰弗里·克拉克，PI 具体目的1：研究Ras效应子的RASSF家族在转化中的作用 Ras癌基因在超过三分之一的人类癌症的发展中起着关键作用。 Ras似乎通过激活多种异源效应蛋白来发挥作用，这些效应蛋白调节控制生长和发育的协同信号传导途径。 在实验上，过量的Ras激活导致剧烈的转化，并且最佳表征的Ras效应蛋白本身是癌蛋白。 然而，Ras的过度活化也可导致细胞经历生长停滞和凋亡。 这表明Ras蛋白可能激活效应子的子集，而不是促进转化，介导生长抑制。 这似乎是合理的假设，这样的效应系统将不得不在转化过程中被破坏，以允许进展到致瘤性。 具体目标2：开发新型Ras作用小分子抑制剂 二十多年来，Ras已被确定为靶向抗癌治疗的主要候选者，但迄今为止，开发Ras特异性抑制剂的尝试被证明是无效的。 最著名的尝试涉及一系列法尼基转移酶抑制剂，这些抑制剂实际上对H-Ras有效，但对家族中最重要的成员K-Ras无效。 最近的工作表明，在人类系统中最重要的Ras效应器的转化是RalGDS组的效应器。 这与鼠系统中的结果形成对比，鼠系统中涉及Rafs作为关键效应子。 尚未描述RalGDS功能的抑制剂。