The Role of FKBP38 in tumorigenesis associated with Tsc deficiency

描述（由申请人提供）：多发性硬化症（TSC）是一种常染色体显性遗传疾病，影响约1/6000的个体。其特征在于在多个器官（包括脑、肾、心脏、肺和皮肤）中发生各种良性肿瘤，通常被归类为错构瘤。尽管其良性性质，TSC的病变往往导致严重的神经系统疾病和器官衰竭，导致患病个体的发病率和死亡率。与TSC相关的基因突变已被定位到两个单独的基因座，TSC 1和TSC 2。TSC 1和TSC 2的基因产物，hamartin和tuberin，形成一个复合物，负调控Rheb，Ras样小GTP结合蛋白。最近发现雷帕霉素的靶点mTOR是Rheb的主要效应子。作为细胞生长的中心调节因子，mTOR通过整合由生长因子和营养条件的变化引发的信号来发挥作用。TSC-Rheb通路和mTOR信号传导之间的联系为TSC 1/TSC 2复合物在细胞生长控制中的作用及其在肿瘤发生中的功能障碍提供了有效的解释。尽管最近的进展，两个关键的问题仍然没有回答我们的理解的致病机制的基础TSC。首先，Rheb如何调节mTOR？第二，mTOR是导致肿瘤发生的唯一介质吗？为了回答这些问题，我们已经确定了一种新的机制，将TSC-Rheb通路与mTOR信号传导和细胞凋亡联系起来。这一令人兴奋的发现促使我们假设Tsc缺陷通过刺激mTOR信号传导和阻止细胞凋亡促进肿瘤发生。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中这两个重要过程的分子基础。本研究计划的长期目标是确定与TSC缺陷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，并为开发治疗药物以治疗和预防这种毁灭性疾病提供分子基础。 公共卫生的相关性：多发性硬化症（TSC）是一种常染色体显性遗传疾病，表现为多器官良性肿瘤的发生。这种疾病是由TSC 1或TSC 2肿瘤抑制基因的失活突变引起的。然而，这两个肿瘤抑制基因的功能障碍如何导致动物和人类的肿瘤发生知之甚少。我们有证据表明，与TSC相关的肿瘤发生可能是由于TSC 1和TSC 2基因缺陷导致细胞增殖和死亡之间的不平衡所致。在这个提议中，我们计划研究一种新的信号转导机制，通过这种机制，两种肿瘤抑制因子控制细胞的生长和死亡。这项研究的成功完成将使我们能够确定潜在的治疗目标，为结节性硬化症和癌症的干预。

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.