The role of ATR in preventing age-related diseases

ATR 在预防年龄相关疾病中的作用

• 批准号: 8677675
• 负责人: Eric J Brown
• 金额: $ 32.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677675
• 关键词: Acute; Adult; Affect; Age; Aging; Appearance; Architecture; Area; Back; Biological Assay; Bone Marrow; Cells; Characteristics; Chromatin; DNA Damage; DNA Double Strand Break; DNA biosynthesis; Data; Development; Disease; Effectiveness; Event; Excision; Failure; Funding; Generations; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Growth Factor; Homeostasis; Immune; Inflammation; Kinetics; Lead; Life; Long-Term Effects; Maintenance; Mediating; Morbidity - disease rate; Mus; Natural regeneration; Oncogenic; Organ; Outcome; Pathology; Pathway interactions; Phase; Phosphotransferases; Physiological; Population; Process; Production; Publishing; Recruitment Activity; Reliance; Research; Role; Signal Pathway; Signal Transduction; Source; Staging; Stem cells; Stress; System; Telomerase; Time; Tissues; United States; age related; base; cell injury; cost; cytokine; exhaustion; genome-wide; inhibitor/antagonist; mortality; novel; pleiotropism; prevent; progenitor; regenerative; research study; response; signal processing; small molecule; stem cell population; tissue regeneration

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.

项目概要 衰老的一般特征是组织结构、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 使用一种新系统删除成年小鼠中的 ATR 检查点激酶进行维护。我们证明了 1) 干细胞消耗和复制需求增加导致再生潜力耗尽 与年龄相关的病变的出现，以及 2) 未能抑制高度受损的积累 细胞可以显着抑制组织再生。后一种机制被认为是组织更新 阻止再生的检查点，直到受损细胞能够被有效清除。最后，我们的初步 结果表明，延迟更新之后立即进入高度刺激阶段，最终 加速退化。在此，我们建议通过定义以下内容来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 干细胞潜力衰弱。为了实现这一目标，将使用亚态 ATR 抑制将 短暂的复制异常变成更长寿的中间体（双链断裂）。该系统将 允许识别选择性复制的细胞群和基因组位点 代偿更新期间的异常。此外，我们建议使用我们的 ATR 条件系统 描述 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。总的来说， 这些研究将确定如何调节补偿性更新的紧急事件以及如何控制这些事件 事件可能导致长期更新潜力下降。