Growth regulatory targets of the Tuberous Sclerosis Complex

描述（由申请人提供）：结节性硬化症（TS）是一种常染色体显性疾病，可在许多组织中引起广泛的良性肿瘤，包括脑、肺、肾、皮肤、眼睛和牙齿。虽然TS很少致命，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。肿瘤可以在一生中出现，在严重的情况下会导致成人肾脏或心脏衰竭。这种疾病非常普遍，影响约1/6000人，或约50,000人在美国人口中。没有治疗方法。大多数TS病例是由编码蛋白质复合物的两个基因TSC1或tsc2之一的功能丧失引起的。TSC1/2复合体通过抑制Rheb的活性介导其许多作用，Rheb是雷帕霉素靶蛋白（TOR）激酶的重要激活剂，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。它在人类中有两个特征明确的靶点，S6K和4EBP，但对果蝇和小鼠的遗传分析表明，这些靶点不能解释结节性硬化症中出现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都是通过Rheb和/或TOR介导的。因此，需要鉴定和表征TSC1/2复合体的其他效应物，以提高我们对这种疾病的分子和细胞基础的理解。本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TSC1/2复合体通过Rheb和TOR介导其所有作用的假设；2)鉴定和鉴定TSC1/2和Rheb功能所需的新基因产物。这些基因被认为是结节性硬化症中细胞生长失调的效应因子，因此构成了该病诊断和治疗的潜在靶点。

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 ~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 orTSC2, 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.