Pathologic and therapeutic implications of Akt attenuation in TSC cells and tumor

Akt 减弱对 TSC 细胞和肿瘤的病理和治疗意义

• 批准号: 7432485
• 负责人: BRENDAN D. MANNING
• 金额: $ 25.56万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-13 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7432485
• 关键词: Affect; Apoptosis; Apoptotic; Attenuated; BAD gene; Bad protein; Benign; Binding; Biochemical Genetics; Biological; Boston; Brain; Cell Cycle Arrest; Cell Death; Cell Survival; Cells; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Condition; Cultured Cells; Cyclin D1; Cyclin E; Cytostatics; DNA Binding; Defect; Diabetes Mellitus; Disease; Disease regression; Disruption; Drug Compounding; Embryo; Event; Exhibits; Eye; Family; Family member; Feedback; Fibroblasts; Gene Targeting; Genes; Genetic; Gleevec; Goals; Growth; Growth Factor; Hamartoma; Heart; Hippocampus (Brain); Human; Imatinib mesylate; Individual; JUN gene; Kidney; Knowledge; Laboratories; Lung; Malignant Neoplasms; Measures; Mediating; Mitochondria; Modeling; Molecular; Mus; Mutation; Nature; Neurologic Manifestations; Neurology; Neurons; Numbers; PDGFRB gene; Pathologic; Pathway interactions; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Predisposition; Proliferating; Property; Proteins; Recurrence; Regulation; Relative (related person); Research Personnel; Rodent Model; Role; Serum; Signal Transduction; Sirolimus; Skin; Syndrome; System; TSC1/2 gene; TSC2 gene; Testing; Therapeutic; Tuberous sclerosis protein complex; Tumor Suppressor Genes; Tyrosine Kinase Inhibitor; Withdrawal; attenuation; body system; c-myc Genes; cell growth; compare effectiveness; cytotoxic; design; early childhood; gene function; human disease; inhibitor/antagonist; mouse model; neoplastic cell; neuronal growth; neuronal survival; novel therapeutics; prevent; programs; receptor; reconstitution; stem; transcription factor; tumor; tumor progression; tumorigenic; vector

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is a tumor syndrome affecting approximately one in 6,000 individuals, most often in early childhood. This clinically severe disease is caused by mutations in one of two tumor suppressor genes, TSC1 and TSC2, whose gene products form a complex. Recent studies by our laboratory and others have found that this complex is a critical negative regulator of the mammalian target of rapamycin (mTOR). Cells and tumors lacking TSC gene function exhibit constitutive mTOR signaling, and this contributes to tumor formation in mouse models of TSC. In addition, this elevated mTOR activity triggers a negative feedback loop in TSC-deficient cells that renders the PI3K-Akt pathway unresponsive to specific growth factors. The PI3K-Akt pathway is a critical cell survival and proliferation pathway that is aberrantly activated in a large percentage of human cancers. Using mouse genetics, we have recently found that feedback inhibition of this pathway limits the growth of TSC tumors. Our central hypothesis is that Akt attenuation upon loss of TSC gene function significantly affects the survival and proliferation properties of TSC cells and tumors. Additionally, as treatment with the mTOR inhibitor rapamycin, which is currently in clinical trials for TSC, can restore Akt signaling in these cells, we predict that this drug will also enhance the survival of TSC cells. The studies described in this proposal will determine the implications of these defects in Akt signaling with an emphasis on identifying novel therapeutic opportunities for the treatment of TSC. The specific aims are: 1) characterize defects in Akt-mediated cell survival signaling in Tsc-deficient cells and tumors and the effects on the apoptotic potential of cells lacking the TSC genes; 2) compare the effectiveness of combination therapy inhibiting both mTOR and the PI3K-Akt pathway to mTOR inhibition alone toward inducing apoptosis in TSC cell culture and mouse models; 3) determine the mechanism of regulation of GSK3 in Tsc-deficient cells and its effects on the growth factor-independent proliferation property of these cells; 4) determine if the defects in Akt signaling extend to Tsc-deficient neurons. A detailed molecular understanding of the signaling defects triggered by functional inactivation of the TSC1/2 complex is critical to the design of proper treatments for TSC and to our knowledge of the wide variety of human diseases, such as sporadic cancers and diabetes, in which this pathway is involved.

描述（由申请人提供）：多发性硬化综合征（TSC）是一种肿瘤综合征，大约每6,000人中就有一人患病，最常见于儿童早期。这种临床上严重的疾病是由两种肿瘤抑制基因之一的突变引起的，TSC 1和TSC 2，其基因产物形成复合物。我们实验室和其他人最近的研究发现，这种复合物是哺乳动物雷帕霉素靶蛋白（mTOR）的关键负调节因子。缺乏TSC基因功能的细胞和肿瘤表现出组成性mTOR信号传导，这有助于TSC小鼠模型中的肿瘤形成。此外，这种升高的mTOR活性触发了TSC缺陷细胞中的负反馈回路，使得PI 3 K-Akt途径对特定生长因子无反应。PI 3 K-Akt通路是一种重要的细胞存活和增殖通路，在大部分人类癌症中被异常激活。利用小鼠遗传学，我们最近发现，反馈抑制这一途径限制了TSC肿瘤的生长。我们的中心假设是，在TSC基因功能丧失后Akt衰减显著影响TSC细胞和肿瘤的存活和增殖特性。此外，由于目前正在进行TSC临床试验的mTOR抑制剂雷帕霉素治疗可以恢复这些细胞中的Akt信号传导，我们预测这种药物也将提高TSC细胞的存活率。本提案中描述的研究将确定Akt信号传导中这些缺陷的影响，重点是确定治疗TSC的新治疗机会。具体目标是：1）表征Tsc缺陷细胞和肿瘤中Akt介导的细胞存活信号传导的缺陷以及对缺乏TSC基因的细胞的凋亡潜力的影响; 2）比较抑制mTOR和PI 3 K-Akt途径两者的组合疗法与单独的mTOR抑制对于在TSC细胞培养物和小鼠模型中诱导凋亡的有效性; 3）确定GSK 3在Tsc缺陷细胞中的调节机制及其对这些细胞的生长因子非依赖性增殖特性的影响; 4）确定Akt信号传导的缺陷是否延伸到Tsc缺陷的神经元。详细了解TSC 1/2复合物功能失活引发的信号传导缺陷，对于设计TSC的适当治疗方法以及我们对该途径所涉及的各种人类疾病（如散发性癌症和糖尿病）的了解至关重要。