The Role of FKBP38 in tumorigenesis associated with Tsc deficiency

FKBP38 在与 Tsc 缺乏相关的肿瘤发生中的作用

基本信息

批准号：
7596289
负责人：
YU JIANG
金额：
$ 28.29万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7596289
关键词：
Address Affect Aggressive behavior Animals Apoptosis Apoptotic Attenuated Benign Binding Brain Cancer cell line Cell Line Cell Proliferation Cell physiology Cells Cessation of life Complex Defect Disease Functional disorder GTP Binding GTP-Binding Proteins GTPase-Activating Proteins Gene Mutation Goals Growth Growth Factor Hamartoma Heart Hereditary Disease Human In Vitro Individual Intervention Kidney Lesion Link Lung Malignant Neoplasms Maps Mediating Mediator of activation protein Modeling Molecular Monomeric GTP-Binding Proteins Morbidity - disease rate Mutation Nature Nutrient Organ Organ failure Pathway interactions Process Proteins Rapamycin-Binding Proteins Regulation Research Role Signal Transduction Sirolimus Skin Starvation TSC1 gene TSC1/2 gene TSC2 gene Tacrolimus Binding Protein 1A Testing Therapeutic Agents Tuberous sclerosis protein complex Tumor Suppressor Genes Tumor Suppressor Proteins base cell growth chemotherapeutic agent deprivation design human FRAP1 protein human TSC1 protein human TSC2 protein in vivo inhibitor/antagonist mTOR Inhibitor mTOR Signaling Pathway mTOR inhibition mortality mutant nervous system disorder novel prevent therapeutic target tumor tumorigenesis

项目摘要

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.

描述（由申请人提供）：结节性硬化症复合物（TSC）是一种常染色体显性遗传疾病，影响了6000名中的大约1个。它的特征是出现各种良性肿瘤，通常被归类为Hamartomas，在多个器官中，包括大脑，肾脏，心脏，肺和皮肤。尽管具有良性的性质，但TSC的病变经常导致严重的神经系统障碍和器官衰竭，从而导致受影响个体的发病率和死亡率。与TSC相关的遗传突变已映射到两个分离的基因座TSC1和TSC2。 TSC1和TSC2，Hamartin和Tuberin的基因产物形成一种复合物，对RHEB进行负调节，Rheb是一种Ras样小GTP结合蛋白。最近发现，雷帕霉素的靶标MTOR是Rheb的主要效应子。作为细胞生长的中心调节剂，MTOR通过整合由生长因子和营养条件变化引发的信号来起作用。 TSC-RHEB途径与MTOR信号传导之间的联系为TSC1/TSC2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。尽管最近取得了进步，但我们对TSC潜在的致病机制的理解仍未得到解决。首先，Rheb如何调节MTOR？其次，MTOR是唯一导致与TSC缺乏症相关的肿瘤发生的介体吗？为了回答这些问题，我们确定了一种新型机制，该机制将TSC-RHEB途径桥接到MTOR信号传导和凋亡中。这一令人兴奋的发现促进了我们假设TSC缺乏症通过刺激MTOR信号传导和预防凋亡来促进肿瘤发生。在本研究计划中，我们将研究TSC-RHEB途径在细胞生长和增殖中控制这两个重要过程的分子基础。该研究计划的长期目标是定义与TSC缺乏相关的肿瘤发生的分子基础。该研究计划的成功完成将有助于理解结节性硬化症复合体，并为开发治疗剂治疗和预防这种毁灭性疾病提供分子基础。公共卫生关系：结节性硬化症复合物（TSC）是一种常染色体显性疾病，由多个器官中的良性肿瘤发生表现出来。疾病状况是由TSC1或TSC2肿瘤抑制基因中的突变灭活引起的。然而，对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。我们有证据表明，与TSC相关的肿瘤发生可能是由于细胞增殖和死亡之间的不平衡引起的，这是由于TSC1和TSC2基因的缺陷。在此提案中，我们计划研究一种新型的信号转导机制，通过该机制，两种肿瘤抑制器控制细胞生长和死亡。这项研究的成功完成将使我们能够确定潜在的治疗靶标，以干预结节性硬化症复合物和癌症。