The role of ATR in preventing age-related diseases

项目摘要 衰老通常表现为组织结构、功能和再生能力的长期丧失 容量。在之前的资助期间，我们探讨了两个关键挑战对长期组织的影响 使用一种新的系统在成年小鼠中删除ATR检查点激酶的维护。我们证明了1) 干细胞磨损和复制需求增加加速了再生潜力的耗尽 出现与年龄相关的病理改变，以及2)未能抑制高度受损的积聚 细胞可以主要抑制组织再生。这一后来的机制被认为是组织更新 在受损细胞被有效清除之前阻止再生的检查点。最后，我们的初选 结果表明，延迟更新之后紧接着是一个高度刺激的阶段，最终 加速退化。在此，我们建议通过定义 促进复制相关DNA损伤的生理条件及其与 削弱了干细胞潜能。为了实现这一目标，将使用亚纯ATR抑制来转换 瞬时复制异常进入更长寿命的中间产物(双链断裂)。这个系统将会 允许识别选择性地对复制敏感的细胞群体和基因组位置 在补偿续期过程中出现异常。此外，我们建议使用我们的ATR条件系统来 描述DNA损伤细胞如何通过外在因素协调不同的再生阶段。 这些因素包括抑制更新的因素和随后刺激更新的因素。总而言之， 这些研究将确定如何监管补偿性续签的紧急情况，以及如何 事件可能会导致长期续期潜力的下降。

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.