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: 7433900
• 负责人: Bruce Alexander Edgar
• 金额: $ 37.8万
• 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/7433900
• 关键词: Accounting; Adult; Affect; Autophagocytosis; Benign; Brain; Cells; Complex; Cytoskeletal Modeling; Diagnosis; Disease; Disseminated Malignant Neoplasm; Drosophila genome; Drosophila genus; Embryo; Employee Strikes; Eye; Genes; Genetic; Genetic Transcription; Growth; Heart; Heart failure; Human; Hypertrophy; Individual; Isotope Labeling; Kidney; Life; Loss of Heterozygosity; Lung; Mass Spectrum Analysis; Mediating; Mental Retardation; Metabolism; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutagens; Mutation; Nutrient; Obstruction; Pathway interactions; Patients; Phenotype; Phosphotransferases; Plague; Population; Predisposition; Protein Biosynthesis; Protein Overexpression; Proteins; Proteome; Proteomics; Research Personnel; Seizures; Sirolimus; Skin; TSC1 gene; TSC1/2 gene; Thinking; Tissues; Tooth structure; Tuberous Sclerosis; Tuberous sclerosis protein complex; base; cell growth; gain of function; genetic analysis; loss of function; programs; tumor

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.

描述（由申请人提供）：结节性硬化症（TS）是一种常染色体显性遗传疾病，会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。尽管 TS 很少致命，但它会导致使人衰弱的并发症，如癫痫、智力低下和心脏梗阻。肿瘤可能在一生中出现，在严重的情况下会导致成人肾衰竭或心力衰竭。这种疾病非常流行，影响约 1/6000 人，即美国人口中约 50,000 人。没有治愈方法。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 复合物通过抑制 Rheb 的活性来介导其许多作用，Rheb 是雷帕霉素靶标 (TOR) 激酶的重要激活剂，而雷帕霉素靶激酶是细胞生长的中央调节剂。 TOR 控制细胞生长所需的多种代谢过程，包括蛋白质合成、营养物质输入、自噬和转录。它在人类中有两个特征明确的靶标：S6K 和 4EBP，但果蝇和小鼠的遗传分析表明，这些靶标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都是通过 Rheb 和/或 TOR 介导的。因此，需要对 TSC1/2 复合物的其他效应子进行鉴定和表征，以增进我们对该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来：1）评估 TSC1/2 复合物通过 Rheb 和 TOR 介导其所有作用的假设； 2) 鉴定并表征 TSC1/2 和 Rheb 功能所需的新基因产物。这些基因预计将成为结节性硬化症中细胞生长失调的效应子，因此构成该疾病诊断和治疗的潜在靶标。