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Aging and Stem Cell Resilience

衰老和干细胞恢复能力

基本信息

批准号：
10209216
负责人：
THOMAS A. RANDO
金额：
$ 55.11万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209216
关键词：
Acetylation Address Adult Age Aging Attention Blood Caloric Restriction Cell Aging Cell Cycle Cell Death Cell Survival Cells Data Diet Dietary Intervention Exhibits Fasting Functional disorder Genetic Models Goals Heterogeneity Histone Deacetylase Histone Deacetylase Inhibitor Homeostasis Impairment In Vitro Individual Injury Intermittent fasting Intervention Ketone Bodies Ketosis Knock-out Laboratories Lead Longevity Mediating Mediator of activation protein Mitotic Molecular Molecular Profiling Muscle Muscle satellite cell Outcome Pathway interactions Phenotype Population Population Decreases Process Publishing Regenerative capacity Resistance Role Signal Pathway Signal Transduction Stress Structure TP53 gene Testing Time Tissues Transgenic Organisms Work age related aged base beta-Hydroxybutyrate biological adaptation to stress exhaustion functional decline in vivo ketogenic diet muscle aging muscle regeneration muscular structure new therapeutic target notch protein novel phosphoproteomics preservation prevent regeneration potential regenerative repaired replication stress resilience response response to injury satellite cell screening self-renewal single-cell RNA sequencing stem cell population stem cells

项目摘要

Stem cells are responsible for homeostasis and repair of many tissues in the body, and stem cell exhaustion is one of the hallmarks of aging. In recent years, work from our group and others has drawn attention to the mechanisms by which the resilience of muscle stem cells (MuSCs) declines with age at the population level and at the single cell level. As one example, we have shown that a signaling pathway involving Notch activation and increased p53 activity prevents MuSCs from undergoing a form of cell death, mitotic catastrophe, as they activated out of quiescence and enter the cell cycle. This Notch/p53 axis declines with age and leads to an increased propensity of aged MuSCs to undergo mitotic catastrophe, leading to a decline in MuSCs over time. Furthermore, in preliminary studies, we have found that quiescent MuSCs exhibit evidence of replicative stress and that an ATR response to that stress prevents cell cycle entry and preserves the MuSC population. We have also found that dietary interventions, in particular fasting and a ketogenic diet, enhance MuSC resilience, perhaps mediated by HDAC activity and p53 acetylation. Together, these observations highlight robust processes to maintain MuSC resilience and prevent stem cell depletion, processes that go awry during the aging process. The primary goals of this proposal are to explore these processes in more detail, to identify the molecular mediators of each, to use unbiased screens to identify as yet unknown mediators, and to pursue rejuvenating interventions that restore resiliency to aged MuSCs. To address these issues, this proposal is divided into three Specific Aims. Aim 1: To examine changes of the Notch/p53 axis as a cause of the age-related reduction of MuSC resilience. We will use novel genetic models to modulate Notch signaling in MuSCs and test for resilience signatures of cells protected against mitotic catastrophe. We will also assess resilient cells for evidence of mediators downstream of p53 using single cell RNA-seq. Aim 2: To examine replicative stress and the ATR response in young and old MuSCs. We will examine a potential downstream mediator of ATR, CDK12, identified in a phosphoproteomic screen, in preserving resilience of the population. We will also test whether this replicate stress response pathway changes with age and protect MuSCs from undergoing mitotic catastrophe when they activate out of quiescence. Aim 3: To elucidate the mechanisms by which ketosis promotes MuSC resilience. We will test for enhancement of resilience using three different ketosis-inducing interventions, and we will test for mechanisms of action based on the well- documented role of the major circulating ketone body, beta-hydroxybutyrate (βHB), as an inhibitor of histone deacetylases (HDACs). We will also test whether ketosis enhances MuSC resilience, at least in part, by promoting p53 activity and preventing mitotic catastrophe. Together, these studies will advance our understanding of the mechanisms of stem cell resiliency and how to enhance the resilience of aged stem cells to promote tissue homeostasis and repair across the lifespan.

干细胞负责体内许多组织的稳态和修复，以及干细胞衰竭