The Role of FKBP38 in tumorigenesis associated with Tsc deficiency

描述(申请人提供)：结节性硬化症(TSC)是一种常染色体显性遗传病，影响大约6000人中的1人。它的特点是发生各种良性肿瘤，通常被归类为错构瘤，位于多个器官，包括大脑、肾脏、心脏、肺和皮肤。尽管TSC的性质是良性的，但TSC的病变往往会导致严重的神经紊乱和器官衰竭，在受影响的个人中导致发病率和死亡率。与TSC相关的基因突变已被定位到两个独立的基因座，TSC1和TSC2。TSC1和TSC2的基因产物Hamartin和tuberin形成一个复合体，负调控Rheb，一种类似RAS的小GTP结合蛋白。新近发现，雷帕霉素的靶点mTOR是Rheb的主要效应因子。作为细胞生长的中央调节因子，mTOR通过整合生长因子和营养条件变化引发的信号发挥作用。TSC-Rheb通路和mTOR信号之间的联系为TSC1/TSC2复合体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。尽管最近取得了进展，但在我们对TSC致病机制的理解中，仍有两个关键问题没有得到回答。首先，RHEB如何监管mTOR？第二，mTOR是与TSC缺乏相关的唯一促进肿瘤发生的介质吗？为了回答这些问题，我们已经确定了一种新的机制，将TSC-Rheb途径与mTOR信号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缺乏通过刺激mTOR信号和防止细胞凋亡来促进肿瘤的发生。在这项研究计划中，我们将研究TSC-Rheb途径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的复杂性，并为开发治疗药物来治疗和预防这种毁灭性的疾病提供分子基础。 公共卫生关系：结节性硬化症(TSC)是一种常染色体显性遗传性疾病，表现为多器官良性肿瘤的发生。这种疾病是由TSC1或TSC2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却知之甚少。我们有证据表明，与TSC相关的肿瘤发生可能是由于TSC1和TSC2基因的缺陷导致细胞增殖和死亡之间的失衡所致。在这个计划中，我们计划研究一种新的信号转导机制，通过这种机制，这两种肿瘤抑制因子同时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干预结节性硬化症和癌症的潜在治疗靶点。

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.