The Role of FKBP38 in tumorigenesis associated with Tsc deficiency

描述（由申请人提供）：结节性硬化症（TSC）是一种常染色体显性遗传疾病，约6000人中有1人患病。它的特点是发生多种良性肿瘤，常被归类为错构瘤，多器官，包括脑、肾、心、肺和皮肤。尽管其本质是良性的，但TSC的病变往往导致严重的神经功能障碍和器官衰竭，导致患者的发病率和死亡率。与TSC相关的基因突变已被定位到两个分离的位点，TSC1和TSC2。TSC1和TSC2的基因产物错构体和tuberin形成一个负调控Rheb（一种ras样小GTP结合蛋白）的复合物。最近发现，雷帕霉素的靶点mTOR是Rheb的主要效应物。作为细胞生长的中枢调节因子，mTOR通过整合生长因子和营养条件变化引发的信号起作用。TSC-Rheb通路与mTOR信号传导之间的联系为TSC1/TSC2复合物在细胞生长控制及其肿瘤发生中的功能障碍的作用提供了有效的解释。尽管最近取得了进展，但在我们对TSC致病机制的理解中，两个关键问题仍未得到解答。首先，Rheb是如何调控mTOR的？第二，mTOR是唯一促进与TSC缺乏相关的肿瘤发生的介质吗？为了回答这些问题，我们发现了一种连接TSC-Rheb通路与mTOR信号传导和细胞凋亡的新机制。这一令人兴奋的发现促使我们假设Tsc缺乏通过刺激mTOR信号传导和阻止细胞凋亡来促进肿瘤发生。在本研究计划中，我们将研究TSC-Rheb通路控制细胞生长和增殖这两个重要过程的分子基础。这项研究计划的长期目标是确定与TSC缺乏相关的肿瘤发生的分子基础。这项研究计划的成功完成将有助于了解结节性硬化症复合体，并为开发治疗和预防这种毁灭性疾病的治疗药物提供分子基础。

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that affects about 1 in 6000 individuals. It is characterized by occurrence of various benign tumors, often classified as hamartomas, in multiple organs, including brain, kidney, heart, lung, and skin. Despite their benign nature, the lesions of TSC often led to severe neurological disorder and organ failure, causing morbidity and mortality in affected individuals. Genetic mutations associated with TSC have been mapped to two separated loci, TSC1 and TSC2. The gene products of TSC1 and TSC2, hamartin and tuberin, form a complex that negatively regulates Rheb, a Ras-like small GTP binding protein. It has been recently found that mTOR, the target of rapamycin, is a major effector of Rheb. As a central regulator of cell growth, mTOR acts by integrating signals initiated by changes in growth factor and nutrient conditions. The connection between the TSC-Rheb pathway and mTOR signaling provides an effective explanation for the role of the TSC1/TSC2 complex in cell growth control and their dysfunction in tumorigenesis. Despite the recent advances, two critical questions remain unanswered in our understanding of pathogenic mechanisms underlying TSC. First, how does Rheb regulate mTOR? Second, is mTOR the only mediator that contributes to tumorigenesis associated with TSC deficiency? In an attempt to answer these questions, we have identified a novel mechanism that bridges the TSC-Rheb pathway to mTOR signaling and apoptosis. This exciting finding promotes us to hypothesize that Tsc deficiency promotes tumorigenesis by stimulating mTOR signaling and preventing apoptosis. In this research plan, we will investigate the molecular basis by which the TSC-Rheb pathway controls these two important processes in cell growth and proliferation. The long term goal of this research plan is to define the molecular basis underlying the tumorigenesis associated with TSC deficiency. Successful completion of this research plan will help to understand the tuberous sclerosis complex and provide molecular basis for developing therapeutic agents to treat and prevent this devastating disease. PUBLIC HEALTH RELVANCE: Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder that is manifested by occurrence of benign tumors in multiple organs. The disease condition is caused by inactivating mutations in either the TSC1 or TSC2 tumor suppressor gene. However, how dysfunction in the two tumor suppressor genes leads to tumorigenesis in animal and human is poorly understood. We have evidence suggest that the tumorigenesis associated with TSC may be caused by an imbalance between cell proliferation and death, owing to defects in the TSC1 and TSC2 genes. In this proposal, we plan to study a novel signal transduction mechanism by which the two tumor suppressors controls both cell growth and death. Successful completion of this study would allow us to identify potential therapeutic target for intervention of the tuberous sclerosis complex and cancer.