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.

项目摘要 衰老通常可以表征为组织结构，功能和再生的长期损失 容量。在上一个资金期间，我们探讨了长期组织的两个主要挑战的影响 使用新型系统维护以删除成年小鼠中的ATR检查点激酶。我们表明1） 通过干细胞损耗耗尽再生潜力，并增加复制需求会加速 与年龄相关的病理的出现，以及2）未能抑制高度损害的积累 细胞可以主要抑制组织再生。这种以后的机制可作为组织更新 检查点可以防止再生，直到可以有效清除损坏的细胞为止。最后，我们的初步 结果表明，延迟更新后立即进行高度刺激阶段，最终 加速变性。在此，我们建议通过定义 促进复制相关的DNA损伤并将这种损害与之相关的生理条件 衰弱的干细胞电位。为了实现这一目标，将使用hydmoldic ATR抑制来转换 瞬态复制异常分为更长寿命的中间体（双链断裂）。这个系统将 允许鉴定细胞群和基因组基因概念，这些基因素位点有选择地易于复制 补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受损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它的因素。在汇总中， 这些研究将确定如何调节补偿性更新的紧急发作以及这些如何调节 事件可能导致长期更新潜力的下降。