CELLULAR PHARMACOLOGY OF RAPAMYCIN

雷帕霉素的细胞药理学

• 批准号: 6124431
• 负责人: ROBERT T ABRAHAM
• 金额: $ 21.11万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-08 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124431
• 关键词: biological signal transduction; cell cycle; cell growth regulation; cell proliferation; cell transformation; enzyme activity; enzyme mechanism; high performance liquid chromatography; immunoprecipitation; neoplasm /cancer pharmacology; neoplastic cell; phosphatidylinositol 3 kinase; phosphorylation; protein sequence; sirolimus; tissue /cell culture; transfection; translation factor

DESCRIPTION: Rapamycin is a bacterially-derived macrolide that is currently undergoing clinical and preclinical evaluations as an immunosuppressant and cancer chemotherapeutic agent. Both the immunosuppressive and anticancer properties of rapamycin are attributed to the inhibition of a signaling pathway required for the passage of proliferating cells from G1 into S phase. A pivotal step toward understanding the anti-proliferative mechanism of rapamycin was the identification of the protein whose function is inhibited when cells are exposed to this drug. The mammalian Target of Rapamycin (mTOR) is a member of a novel family of high molecular weight kinases termed phosphatidylinositol 3-kinase-related kinases (PIKKs). The members of the PIKK family play crucial roles in cell-cycle regulation and chromosome maintenance, and their dysfunction leads to disregulated growth, genomic instability, and cancer. The overall objectives of this proposal are to define the signaling pathway governed by mTOR, and to identify the cell-cycle-related parameters that determine sensitivity or resistance of transformed cells to the anti-proliferative effects of rapamycin. The preliminary studies offer biochemical and genetic evidence that mTOR regulates the translation of mRNAs whose protein products are needed to drive the cell through G1 and into S phase. The current project will extend this research through implementation of three specific aims: (1) to define the role of PHAS-1 in cell growth inhibition by rapamycin, (2) to elucidate upstream regulators of mTOR function in mitogen-stimulated cells, (3) to investigate the interactions of the mTOR-dependent signaling pathway with the cell-cycle control machinery in nontransformed and transformed cells. The completion of these aims may significantly advance ther knowledge of the cellular pharmacology of rapamycin, and will facilitate the development of novel antiproliferative agents targeted against mTOR itself or other components of the mTOR-dependent signaling pathway.

描述：雷帕霉素是一种细菌衍生的大环内酯，目前 作为一种免疫抑制剂进行临床和临床前评估 癌症化疗药物。免疫抑制和抗癌 雷帕霉素的特性归因于对一种信号的抑制 增殖细胞从G1期进入S所需的途径 相位。了解抗增殖机制的关键一步 雷帕霉素的作用是鉴定其功能是 当细胞暴露在这种药物中时，就会受到抑制。哺乳动物的靶子 雷帕霉素(MTOR)是一个新的高分子量家族的成员。 称为磷脂酰肌醇3-激酶相关的激酶(PIKKs)。这个 Pikk家族的成员在细胞周期调控和 染色体的维持，以及它们的功能障碍导致了不受控制的生长， 基因组不稳定和癌症。这项提案的总体目标 是定义由mTOR控制的信号通路，并确定 决定细胞周期相关参数的敏感性或抵抗力 转化细胞对雷帕霉素的抗增殖作用。这个 初步研究提供了生化和遗传证据表明mTOR 调节其蛋白质产物所需的mRNAs的翻译 使细胞通过G1期，进入S期。当前项目将扩展 本研究通过实施三个具体目标：(1)明确 PHAS-1在雷帕霉素抑制细胞生长中的作用，(2)阐明 丝裂原刺激细胞中mTOR功能的上游调节因子，(3)到 研究mTOR依赖的信号通路与 未转化细胞和转化细胞中的细胞周期控制机制。 这些目标的实现可能会极大地促进对 雷帕霉素的细胞药理作用，并将促进 针对mTOR本身或其他靶点的新型抗增殖药物 MTOR依赖的信号通路的组成部分。