Growth regulatory targets of the Tuberous Sclerosis Complex

结节性硬化症复合体的生长调节目标

基本信息

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
项目类别：
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

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

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项目摘要

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疾病，可在许多组织中引起广泛的良性肿瘤，包括大脑，肺，肾脏，皮肤，眼睛，眼睛和牙齿。尽管TS很少致命，但会导致令人衰弱的并发症，例如癫痫发作，智力低下和心脏阻塞。肿瘤可能一生都会出现，在严重的情况下会导致成人肾脏或心力衰竭。该疾病高度普遍，影响约1/6000人，或者在美国人口中约有50,000人。无法治愈。大多数TS的情况是由两个基因TSC1 ORTSC2之一的功能丧失引起的，该基因编码蛋白质复合物。 TSC1/2复合物通过抑制Rheb的活性（Rheb的活性），Rheb的活性（Rheb（Rheb）的活性是 - 拉氨霉素（TOR）激酶的必不可少的活化剂，后者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，养分进口，自噬和转录。它在人类，S6K和4EBP中具有两个良好的靶标，但是果蝇和小鼠的遗传分析表明，这些靶标不能解决结节性硬化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，需要鉴定和表征TSC1/2复合物的其他效应子，以促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介导其所有效应的假设，以及； 2）识别并表征TSC1/2和RHEB功能所需的新基因产品。预计这种基因将是结节性硬化症中细胞生长失调的效应因子，因此构成了疾病诊断和治疗的潜在靶标。