Determining the critical in vivo roles of mTOR in cancer

描述(由申请人提供)：我们对细胞信号通路的电路很感兴趣，我们的长期目标是确定哪些信号连接对肿瘤的发展至关重要。我们目前将工作重点放在mTOR网络上，因为大量最近的研究预测，mTOR信号的解除调控是癌症发病机制中的重要一步。总而言之，这些研究认为，mTOR蛋白激酶从许多不同的输入接收调节信号，然后将这些信号传递给广泛的效应器。基于这些研究，一种原型mTOR-抑制剂已被推向临床试验，作为一种抗癌治疗药物，尽管目前仍不清楚该抑制剂是如何发挥作用的，也不清楚mTOR与肿瘤形成的相关性。在这项提案中，我们的目标是定义mTOR在癌症中的关键作用。在指导阶段，我们结合遗传学、生物化学和RNAi技术来研究mTOR在一般肿瘤发生中的作用。这一阶段旨在提供过渡到独立研究岗位所需的广泛监督培训。在独立阶段，我们(1)研究mTOR在特定癌症中的作用，(2)确定与癌症相关的关键mTOR衍生信号，(3)使用新的基于慢病毒的RNAi技术来寻找潜在的抗癌药物靶点。我们相信，我们的研究将阐明mTOR与人类癌症的相关性，并有助于设计抑制mTOR信号转导的策略，作为癌症患者的治疗手段。 新出现的证据表明，一种名为mTOR的蛋白质的异常调节是癌症发病机制中的关键步骤。在这项建议中，我们采取了多学科的方法，利用最先进的体外和体内技术来(1)研究mTOR在癌症中的作用，(2)促进基于mTOR的治疗的发展。由于mTOR抑制剂被认为是很有前途的抗癌治疗药物，这吸引了制药行业的大量投资，我们的研究旨在为此类药物的合理开发和使用提供重要信息。

DESCRIPTION (provided by applicant): We are interested in the circuitry of cellular signaling pathways and our long-term objective is to define which signaling connections are critical for tumor development. We are currently focusing our efforts on the mTOR network because numerous recent studies predict that deregulation of mTOR signaling is an important step in the pathogenesis of cancer. Collectively, these studies argue that the mTOR protein kinase receives regulatory signals from many diverse inputs and subsequently transmits these signals to a wide array of effectors. Based on these studies, a prototype mTOR-inhibitor has been propelled into clinical trials as an anti-cancer therapeutic, although it is still not clear how that inhibitor works or what the relevance of mTOR is to tumor formation. In this proposal, our goal is to define the critical roles of mTOR in cancer. In the mentored phase, we combine genetics, biochemistry, and RNAi technology to investigate the role of mTOR in general tumorigenesis. This phase is designed to provide extensive supervised training necessary for transitioning to and independent research position. In the independent phase, we (1) investigate the role of mTOR in specific cancers, (2) determine the key mTOR-derived signals relevant in cancer, and (3) use novel lentiviral-based RNAi technologies to search for potential anti-cancer drug targets. We believe our study will shed light on the relevance of mTOR in human cancer and help to design strategies for inhibiting mTOR signaling as a treatment for cancer patients. Emerging evidence indicates that aberrant regulation of a protein called mTOR is a critical step in the pathogenesis of cancer. In this proposal, we take a multidisciplinary approach that exploits state-of-the-art in vitro and in vivo technologies to (1) study the role of mTOR in cancer and (2) to foster development of mTOR-based therapeutics. Because mTOR- inhibitors are speculated to be promising anti-cancer therapeutics and this is attracting large investments from the pharmaceutical industry, our study is designed to provide important information regarding the rational development and use of such drugs.