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。我们目前将重点放在mTOR网络上，因为许多最近的研究预测mTOR信号的解除管制是癌症发病机制的重要一步。总的来说，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，随后将这些信号传递给广泛的效应器。基于这些研究，一种mTOR抑制剂的原型已经被推进到临床试验中，作为一种抗癌疗法，尽管尚不清楚这种抑制剂是如何起作用的，或者mTOR与肿瘤形成的相关性是什么。在这个提案中，我们的目标是确定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职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mTOR衍生的关键信号，(3)使用基于慢病毒的新型RNAi技术寻找潜在的抗癌药物靶点。我们相信我们的研究将揭示mTOR在人类癌症中的相关性，并有助于设计抑制mTOR信号传导的策略，作为癌症患者的治疗方法。

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.