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: 8236593
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236593
• 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; computerized data processing; cost; cytokine; exhaustion; genome-wide; inhibitor/antagonist; mortality; novel; pleiotropism; prevent; progenitor; regenerative; research study; response; small molecule; stem cell population; tissue regeneration

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.

描述（由申请人提供）：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。在之前的资助期间，我们使用一种新的系统来删除成年小鼠中的 ATR 检查点激酶，探讨了两个关键挑战对长期组织维护的影响。我们发现：1）通过干细胞消耗和复制需求增加而耗尽再生潜力会加速与年龄相关的病理的出现，2）未能抑制高度受损细胞的积累会显着抑制组织再生。后一种机制被认为是组织更新检查点，可防止再生，直到受损细胞被有效清除。最后，我们的初步结果表明，延迟更新后立即进入高度刺激阶段，最终加速退化。在此，我们建议通过定义促进复制相关 DNA 损伤的生理条件并将这种损伤与衰弱的干细胞潜力联系起来，进一步发展这些研究领域。为了实现这一目标，亚态 ATR 抑制将用于将短暂的复制异常转化为寿命更长的中间体（双链断裂）。该系统将允许识别在代偿更新期间选择性地易受复制异常影响的细胞群和基因组位点。此外，我们建议使用我们的 ATR 条件系统来表征 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。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。 公共卫生相关性：与年龄相关的疾病是美国发病率和死亡率的主要原因。这些疾病的发生很大程度上受到器官维护和组织再生有效性的影响。在本提案中，我们描述了实验，以更好地确定随着年龄增长再生潜力减弱的原因，并研究在组织完整性严重丧失后用于更新组织的机制。