Growth regulatory targets of the Tuberous Sclerosis Complex

结节性硬化症复合体的生长调节目标

• 批准号: 7131928
• 负责人: Bruce Alexander Edgar
• 金额: $ 38.93万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7131928
• 关键词: Drosophilidae; genes; genetics; human; neoplasm /cancer; proteins; tuberous sclerosis

DESCRIPTION (provided by applicant): Tuberous sclerosis (TS) is an autosomal dominant disease that causes widespread benign tumors in many tissues including the brain, lung, kidney, skin, eyes, and teeth. Although TS is rarely fatal it causes debilitating complications such as seizures, mental retardation, and heart obstruction. Tumors can arise throughout life, and in severe cases cause kidney or heart failure in adults. The disease is highly prevalent, affecting approximately 1/6000 individuals, or about 50,000 in the US population. There is no cure. Most cases of TS are caused by loss of function in one of two genes, TSC1 or TSC2, which encode a protein complex. The TSC1/2 complex mediates many of its effects by inhibiting the activity of Rheb, an essential activator of the Target-Of-Rapamycin (TOR) kinase, which is a central regulator of cell growth. TOR controls diverse metabolic processes required for cell growth including protein synthesis, nutrient import, autophagy, and transcription. It has two well-characterized targets in humans, S6K and 4EBP, but genetic analysis in Drosophila and mice indicate that these targets cannot account for the striking overgrowth phenotypes that occur in tuberous sclerosis. Moreover, it is has not been demonstrated that all of the downstream effects of TSC mutation are mediated via Rheb and/or TOR. Hence the identification and characterization of additional effectors of TSC1/2 complex is required to advance our understanding of the molecular and cellular basis of this disease. This project will use genetic and proteomic approaches in Drosophila and human cells to: 1) Evaluate the hypothesis that the TSC1/2 complex mediates all of its effects via Rheb and TOR, and; 2) Identify and characterize new gene products required for TSC1/2 and Rheb function. Such genes are expected to be effectors of deregulated cell growth in tuberous sclerosis, and as such constitute potential targets for diagnosis and treatment of the disease.

描述（由申请人提供）：脑硬化症（TS）是一种常染色体显性遗传疾病，可导致许多组织（包括脑、肺、肾、皮肤、眼睛和牙齿）中广泛存在的良性肿瘤。虽然TS很少是致命的，但它会引起使人衰弱的并发症，如癫痫发作、智力迟钝和心脏阻塞。肿瘤可以在整个生命中出现，严重的情况下会导致成年人的肾衰竭或心力衰竭。该疾病是高度流行的，影响约1/6000的个体，或在美国人口中约50，000。没有解药。大多数TS病例是由编码蛋白质复合物的两个基因之一TSC 1或TSC 2的功能丧失引起的。TSC 1/2复合物通过抑制Rheb的活性来介导其许多作用，Rheb是雷帕霉素靶点（TOR）激酶的必需激活剂，雷帕霉素靶点（TOR）激酶是细胞生长的中心调节剂。TOR控制细胞生长所需的多种代谢过程，包括蛋白质合成、营养输入、自噬和转录。它在人类中有两个明确的靶点，S6 K和4 EBP，但在果蝇和小鼠中的遗传分析表明，这些靶点不能解释结节性硬化症中发生的惊人的过度生长表型。此外，尚未证明TSC突变的所有下游效应均通过Rheb和/或TOR介导。因此，需要鉴定和表征TSC 1/2复合物的其他效应物，以促进我们对这种疾病的分子和细胞基础的理解。该项目将在果蝇和人类细胞中使用遗传和蛋白质组学方法：1）评估TSC 1/2复合物通过Rheb和TOR介导其所有作用的假设; 2）鉴定和表征TSC 1/2和Rheb功能所需的新基因产物。预期这些基因是结节性硬化症中细胞生长失调的效应子，因此构成了诊断和治疗该疾病的潜在靶点。