The role of ATR in preventing age-related diseases

描述（由申请人提供）：衰老通常可以被描述为组织结构、功能和再生能力的长期丧失。在之前的资助期内，我们使用一种新型系统在成年小鼠中删除ATR检查点激酶，探索了两个关键挑战对长期组织维持的影响。我们发现：1)再生潜能的耗尽，通过干细胞消耗和增加的复制需求，加速了年龄相关病理的出现；2)未能抑制高度受损细胞的积累，可以主要抑制组织再生。这种后一种机制被认为是组织更新检查点，阻止再生，直到受损细胞被有效清除。最后，我们的初步结果表明，延迟的更新紧接着是一个高度刺激的阶段，最终加速了退化。在此，我们建议通过定义促进复制相关DNA损伤的生理条件，并将这种损伤与干细胞潜能减弱联系起来，进一步发展这些研究领域。为了实现这一目标，亚形态ATR抑制将用于将短暂的复制异常转化为更长寿的中间产物（双链断裂）。该系统将允许在代偿性更新过程中对复制异常选择性敏感的细胞群和基因组位点的鉴定。此外，我们建议使用我们的atr条件系统来表征dna损伤细胞如何通过外部因素协调再生的不同阶段。这些因素包括抑制细胞更新和随后刺激细胞更新的因素。总的来说，这些研究将确定如何调节代偿性更新的紧急事件，以及这些事件如何导致长期更新潜力的下降。

DESCRIPTION (provided by applicant): Aging can be generally characterized as the long-term loss of tissue architecture, function and regenerative capacity. In the previous funding period, we explored the effects of two key challenges to long-term tissue maintenance using a novel system to delete the ATR checkpoint kinase in adult mice. We showed 1) that exhaustion of regenerative potential through stem cell attrition and increased replicative demand accelerates the appearance of age-related pathologies, and 2) that failure to suppress the accumulation of highly-damaged cells can dominantly inhibit tissue regeneration. This later mechanism putatively serves as a tissue renewal checkpoint that prevents regeneration until damaged cells can be effectively cleared. Finally, our preliminary results indicate that delayed renewal is immediately followed by a highly stimulatory phase that ultimately accelerates degeneration. Herein, we propose to further develop these research areas by defining the physiological conditions that promote replication-associated DNA damage and correlating this damage with debilitated stem cell potential. To accomplish this goal, hypomorphic ATR suppression will be used to convert transient replication abnormalities into more long-lived intermediates (double strand breaks). This system will permit the identification of both cell populations and genomic loci that are selectively susceptible to replication abnormalities during compensatory renewal. In addition, we propose to use our ATR-conditional system to characterize how DNA-damaged cells coordinate the distinct phases of regeneration through extrinsic factors. These factors include ones that that inhibit renewal and those that subsequently stimulates it. In aggregate, these studies will determine how urgent episodes of compensatory renewal are regulated and how these events can lead to the decline of long-term renewal potential. PUBLIC HEALTH RELEVANCE: Age-associated pathologies are a major contributor to morbidity and mortality in the United States. Occurrence of these diseases is strongly influenced by the effectiveness of organ maintenance and tissue regeneration. In this proposal, we describe experiments to both better define the causes of debilitated regenerative potential with age and investigate the mechanisms used to renew tissues following acute loss of tissue integrity.