Dysfunctional Telomeres, Checkpoints and Aging

描述(申请人提供)：端粒是染色体上特殊的顶端结构，在衰老、癌症和基因组稳定方面发挥重要作用。随着细胞的每次分裂，端粒逐渐变短，当达到关键阶段时，它们会发出信号让细胞停止分裂。这一过程可能会防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(如p53和ATM)发生突变时，端粒就会变得严重缩短和功能失调。我们最近的发现将端粒功能障碍与联合端粒酶ATM突变小鼠模型中的前体/干细胞耗尽和加速衰老联系起来，为探索端粒功能障碍导致衰老、器官动态平衡和肿瘤发生的分子机制提供了一个独特的机会和遗传平台。我们假设，由于mTerc和ATM缺陷而导致端粒极度短小和检查点反应缺陷的小鼠将更容易加速衰老或肿瘤发生，这取决于P53的状态。我们还认为，这些小鼠不同器官间端粒酶活性的重建将取决于重建时基因组的状态，要么强烈促进器官特异性肿瘤的进展，要么挽救器官干细胞/祖细胞耗竭的表型，同时抑制肿瘤的发生。最后，对加速衰老和前体/干细胞耗竭的复合突变小鼠的原代细胞和组织中导致P53功能激活的途径的详细分子特征将剖析参与衰老过程和器官动态平衡的分子途径。

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.