Dysfunctional Telomeres, Checkpoints and Aging

描述（申请人提供）：端粒是染色体上的特殊封顶结构，在衰老、癌症和基因组稳定中起重要作用。随着每次细胞分裂，端粒逐渐缩短，以至于在到达关键阶段时，它们发出信号让细胞停止分裂。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（如p53和ATM）发生突变时，端粒就会严重缩短和功能失调。我们最近在端粒酶Atm联合突变小鼠模型中发现端粒功能障碍与前体/干细胞耗竭和加速衰老有关，这为探索端粒功能障碍促进衰老、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学平台。我们假设，由于mTerc和Atm缺乏而导致端粒极短和检查点反应缺陷的小鼠将倾向于加速衰老或肿瘤发生，这取决于p53的状态。我们还认为，端粒酶活性在这些小鼠不同器官区室的重组，取决于重组时基因组的状态，要么强烈促进器官特异性肿瘤进展，要么挽救器官干细胞/祖细胞耗竭表型，并抑制肿瘤发生。最后，在这些加速衰老和前体/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表征将剖析参与衰老和器官稳态过程的分子途径。

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.