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(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，可导致脑、肺、肾、皮肤、眼睛和牙齿等许多组织中广泛的良性肿瘤。虽然TS很少致命，但它会导致癫痫发作、智力低下和心脏阻塞等令人衰弱的并发症。肿瘤可能发生在一生中，在严重的情况下会导致成年人的肾功能或心力衰竭。这种疾病非常流行，影响到6000人中的1人，约占美国人口的50,000人。没有治愈的方法。大多数TS是由编码蛋白质复合体的两个基因TSC1或TSC2中的一个功能丧失引起的。TSC1/2复合体通过抑制Rheb的活性来调节其许多作用，Rheb是雷帕霉素靶标(TOR)激酶的基本激活剂，Rheb是细胞生长的中央调节因子。Tor控制细胞生长所需的各种代谢过程，包括蛋白质合成、营养输入、自噬和转录。它在人类中有两个很好的靶点，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，需要对TSC1/2复合体的其他效应因子进行鉴定和表征，以促进我们对该病分子和细胞基础的了解。该项目将在果蝇和人类细胞中使用遗传学和蛋白质组学方法：1)评估TSC1/2复合体通过Rheb和Tor介导其所有作用的假设；2)鉴定和表征TSC1/2和Rheb功能所需的新基因产物。这些基因有望成为结节性硬化症失控细胞生长的效应者，并因此成为诊断和治疗该疾病的潜在靶点。