Dysfunctional Telomeres, Checkpoints and Aging

功能失调的端粒、检查点和衰老

• 批准号: 7065017
• 负责人: Kwok Kin Wong
• 金额: $ 28.63万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7065017
• 关键词: DNA repair; aging; antineoplastics; apoptosis; ataxia telangiectasia; cell age; cell differentiation; chemoprevention; developmental genetics; gene mutation; genetically modified animals; histopathology; laboratory mouse; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplastic transformation; oxidative stress; p53 gene /protein; stem cells; tamoxifen; telomerase; telomere; tissue /cell culture

DESCRIPTION (provided by applicant): Telomeres are specialized capping structures on chromosomes that play important roles in aging, cancer and genome stability. With each cell division, telomeres progressively shorten such that upon reaching a critical stage, they signal cells to stop dividing. This process likely prevents cells from acquiring mutations that may result in cancer or aging. When mutations occur in crucial genes that regulate telomere maintenance or checkpoint responses (such as p53 and ATM), telomeres become critically shortened and dysfunctional. Our recent findings linking telomere dysfunction to precursor/stem cell depletion and accelerated aging in the combined telomerase Atm mutant mouse model provide a unique opportunity and genetic platform to explore the molecular mechanisms by which telomere dysfunction contributes to aging, organ homeostasis and tumorigenesis. We hypothesize that mice engineered to have critically short telomeres and defective checkpoint responses due to mTerc and Atm deficiency will be predisposed to either accelerated aging or tumorigenesis depending on p53 status. We also believe that reconstitution of telomerase activity in different organ compartments of these mice will, depending on the state of the genome at the time of the reconstitution, either strongly promote organ specific tumor progression or rescue the organ stem/progenitor cell depletion phenotype as well as suppressing tumorigenesis. Lastly, detailed molecular characterization of pathways leading to activation of p53 function in primary cells and tissues from these compound mutant mice with accelerated aging and precursor/stem cell depletion will dissect the molecular pathways that are involved in the process of aging and organ homeostasis.

描述（由申请人提供）：端粒是染色体上的特殊加帽结构，在衰老、癌症和基因组稳定性中发挥重要作用。随着每次细胞分裂，端粒逐渐缩短，达到关键阶段后，它们会向细胞发出停止分裂的信号。这个过程可能会阻止细胞获得可能导致癌症或衰老的突变。当调节端粒维持或检查点反应的关键基因（例如 p53 和 ATM）发生突变时，端粒会严重缩短并出现功能障碍。我们最近在联合端粒酶 Atm 突变小鼠模型中将端粒功能障碍与前体/干细胞耗竭和加速衰老联系起来，为探索端粒功能障碍导致衰老、器官稳态和肿瘤发生的分子机制提供了独特的机会和遗传平台。我们假设，由于 mTerc 和 Atm 缺陷而被改造为具有极短端粒和缺陷检查点反应的小鼠将容易加速衰老或肿瘤发生，具体取决于 p53 状态。我们还相信，根据重建时基因组的状态，这些小鼠不同器官区室中端粒酶活性的重建将强烈促进器官特异性肿瘤进展或挽救器官干/祖细胞耗竭表型如抑制肿瘤发生。最后，对这些具有加速衰老和前体/干细胞耗竭的复合突变小鼠的原代细胞和组织中 p53 功能激活途径的详细分子特征分析，将剖析参与衰老和器官稳态过程的分子途径。