The role of ATR in preventing age-related diseases

项目摘要 衰老通常可以表征为组织结构、功能和再生能力的长期丧失。 容量在上一个资助期，我们探讨了两个关键挑战对长期组织的影响。 使用新系统删除成年小鼠中的ATR检查点激酶来维持。我们展示了1）， 通过干细胞损耗和增加的复制需求加速再生潜力的耗尽 与年龄相关病理学的出现，和2）未能抑制高度损伤的 细胞可以主要抑制组织再生。这后来的机制pupletion作为一个组织更新 检查点，防止再生，直到损坏的细胞可以有效地清除。最后，我们初步的 结果表明，延迟更新之后立即是一个高度刺激的阶段， 加速退化。在此，我们建议进一步发展这些研究领域， 促进复制相关DNA损伤的生理条件，并将这种损伤与 干细胞潜能减弱为了实现这一目标，将使用亚纯ATR抑制来转换 瞬时复制异常转化为更长寿命的中间体（双链断裂）。该系统将 允许鉴定选择性地易于复制的细胞群体和基因组基因座 代偿性更新期间的异常。此外，我们建议使用我们的ATR条件系统， 表征DNA损伤的细胞如何通过外在因素协调再生的不同阶段。 这些因素包括抑制更新的因素和随后刺激更新的因素。 这些研究将确定补偿性更新的紧急事件是如何调节的，以及这些事件是如何发生的。 事件可能导致长期更新潜力的下降。

Project Summary 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 stimulate 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.