Uncovering molecular effectors of mammalian aging

揭示哺乳动物衰老的分子效应因素

• 批准号: 9788219
• 负责人: AMY JO WAGERS
• 金额: $ 118.3万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788219
• 关键词: Age; Aging; Alleles; Animals; Automobile Driving; Biological; Biology; Blood; Cardiovascular system; Cell Separation; Cell Transplantation; Cell Transplants; Cells; Cellular Stress; Chronic; Complex; Degenerative Disorder; Deterioration; Disease; Event; Exposure to; Functional disorder; Generations; Genes; Genetic; Genome; Human; In Situ; Individual; Knock-out; Knowledge; Life; Maintenance; Mediating; Mediator of activation protein; Medical; Methods; Molecular; Mus; Musculoskeletal; Mutation; Nerve Degeneration; Organ; Pathology; Pathway interactions; Phenotype; Physiology; Regenerative Medicine; Risk Factors; Role; Skeletal Muscle; Societies; Stem cells; System; Technology; Testing; Tissues; Work; body system; cell behavior; combinatorial; gene function; gene therapy; genetic approach; genome editing; in vivo; innovation; insight; novel; novel therapeutics; programs; regenerative; repaired

Project Summary Aging is the single largest risk factor for most chronic degenerative diseases, including cardiovascular, musculoskeletal and neurodegenerative dysfunctions, and age-associated diseases now represent the most rapidly growing unmet medical need in our society. Yet, while certain “hallmarks of aging” have been defined, the critical molecular mediators that drive (and oppose) mammalian aging phenotypes have yet to be systematically explored, due in part to the technological challenges of applying classic functional genetic approaches, which require the laborious generation and aging(!) of complex gene-specific germline and conditional knockout alleles, to studies of aging physiology. As this substantial knowledge gap presents a significant impediment to developing new therapies for human aging pathologies, we aim in this project to establish a new, more facile approach to interrogating the genes and pathways that regulate mammalian organ function and repair throughout life. Our approach will take advantage of a unique in vivo genome editing system through which we can experimentally induce programmable mutations into the genomes of stem cells in the blood and skeletal muscle in intact animals, without the requirement for stem cell isolation and transplantation. By targeting endogenous stem cells, we allow for the maintenance and propagation of these mutations but circumvent the need to remove these cells their native biological niche, which can induce cellular stress and alter stem cell behavior by exposure to non-physiological ex vivo conditions. We also enable rapid testing of potential combinatorial gene effects, in multiple genetic backgrounds and in mice of various ages. Thus, our approach provides a more powerful, and higher throughput, view into the molecular effectors of organismal aging, which will allow us to test previously unapproachable hypotheses regarding the impact of somatic mutagenic events in aging organ systems and to identify novel regulators that may drive the precocious onset of, or mediate protection from, degenerative phenotypes across organ systems. Taken together, our work will yield new platform technologies for interrogating mammalian gene functions in vivo, new insights into fundamental mechanisms of aging physiology and regenerative biology, and new and potentially broadly useful methods for effecting genetic therapies in situ.

项目摘要 对于大多数慢性退化性疾病，包括心血管，衰老是最大的危险因素 肌肉骨骼和神经退行性功能障碍以及与年龄相关的疾病现在最多 我们社会迅速增长的未满足的医疗需求。然而，尽管已经定义了某些“衰老的标志”，但 驱动（和反对）哺乳动物衰老表型的关键分子介质尚未 系统地探索，部分是由于应用经典功能通用的技术挑战 方法，需要复杂基因特异性种系的实验室产生和衰老（！） 有条件的基因敲除等位基因，研究生理衰老的研究。因为这个大量知识差距提出了 为开发针对人类衰老病理的新疗法的重大障碍，我们的目标是 建立一种新的，更轻松的方法来询问调节哺乳动物器官的基因和途径 一生的功能和维修。 我们的方法将利用一个独特的体内基因组编辑系统，我们可以通过它 实验性地诱导可编程突变进入血液和骨骼中干细胞的基因组 完整动物的肌肉，无需干细胞分离和移植。通过定位 内源性干细胞，我们允许维护和传播这些突变，但要绕过 需要去除它们的天然生物生物位，这些细胞可以诱导细胞应激并改变干细胞 通过暴露于非生理的离体条件来行为。我们还可以快速测试潜力 组合基因作用，在多种遗传背景和各个年龄的小鼠中。那，我们的方法 为有机衰老的分子效应提供更强大，更高的吞吐量，该视图 将允许我们检验以前关于体细胞诱变影响的不可接受的假设 在老化器官系统中，并确定可能推动或介导的早熟发作的新型调节剂 防止器官系统中的退化表型。 综上所述，我们的工作将产生新的平台技术来询问哺乳动物基因功能 在体内，对衰老生理学和再生生物学的基本机制的新见解以及新的和新的 潜在的有用的方法来实现基因疗法的原位。