Mechanisms of Hematopoietic Stem Cell and Blood aging

造血干细胞与血液衰老的机制

• 批准号: 10487436
• 负责人: Emmanuelle Passegue
• 金额: $ 51.07万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487436
• 关键词: Address; Affect; Age; Aging; Anabolism; Anemia; Animals; Automobile Driving; Autophagocytosis; Biogenesis; Biology; Biology of Aging; Blood; Blood Cells; Bone Marrow; Brain; Bromodeoxyuridine; Cell Cycle; Cell Cycle Regulation; Cell Respiration; Cells; Cellular Metabolic Process; ChIP-seq; Chronic; Complex; DNA Damage; DNA Maintenance; Dactinomycin; Defect; Dependence; Development; Disease; Elderly; Environmental Risk Factor; Epigenetic Process; Erythroid; Exposure to; Fasting; Free Ribosome; Functional disorder; Gene Expression Regulation; Genetic; Genomic Instability; Glucose; Goals; Helicase Gene; Hematologic Neoplasms; Hematopoiesis; Hematopoietic System; Hematopoietic stem cells; Immune; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Label; Lead; Life; Link; Longevity; Lymphoid; Maintenance; Marrow; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Organism; Output; Pathway interactions; Physiologic pulse; Predisposition; Process; Production; Proteins; Recycling; Regulation; Rejuvenation; Reporter; Resistance; Resolution; Ribosomal DNA; Ribosomal Proteins; Ribosomes; Role; Secondary to; Signal Transduction; Stress; System; Systems Biology; TP53 gene; Testing; Tissues; Translations; Transplantation; Work; age related; aged; biological adaptation to stress; bone aging; cdc Genes; comparative; design; exhaustion; experimental study; fitness; functional decline; functional improvement; glucose uptake; hematopoietic hierarchy; hematopoietic stem cell aging; immunosenescence; improved; in vivo; inflammatory milieu; insight; insulin sensitivity; metabolomics; novel; progenitor; programs; proteostasis; regeneration potential; replication stress; response; self-renewal; stem cell function; stem cells

PROJECT DESCRIPTION The hallmarks of the aging blood system, such as chronic inflammatory disorders, anemia, immunosenescence and hematological malignancies, result in large part from hematopoietic stem cell (HSC) dysfunction. Age-associated loss of HSC function is linked to metabolic deregulation, increased dependence on autophagy, loss of epigenetic fidelity, replication stress-associated genomic instability, and chronic exposure to local inflammation in the aged bone marrow (BM) niche microenvironment. However, these remain largely descriptive features of HSC aging. This project aims to develop a coherent and mechanistic model of how these extrinsic signals and intrinsic molecular mediators promote old HSC dysfunction, ultimately suggesting actionable targets for rejuvenation interventions. In Aim 1, we will test the hypothesis that autophagy engagement is a prosurvival stress-response mechanism that protects a subset of old HSCs from chronic inflammation in the aged BM niche. Specifically, we will probe whether increased oxidative metabolism in old HSCs functions to compensate for decreased glucose utilization due to chronic inflammation-induced insulin resistance. Insulin resistance is increasingly appreciated to affect non-canonical tissues, such as the brain, where it has been connected to age-associated inflammation and neurodegeneration. We will establish how the inflamed marrow milieu directly promotes insulin/IGF-1 pathway resistance, how this drives autophagy engagement and metabolic adaptation in a subset of old HSCs, and whether old HSC regenerative potential can be improved through fasting/refeeding interventions via normalization of insulin sensitivity and glucose uptake. In Aim 2, we will further dissect how replication stress contributes to the functional exhaustion of aged HSCs. In particular, we will focus on the fragile ribosomal DNA (rDNA) loci, which are severely impacted by replication stress in old HSCs, interfering with ribosome biogenesis. Defects in ribosome biogenesis lead to an accumulation of free ribosomal proteins triggering activation of a p53-dependent nucleolar stress response, as well as defects in protein translation, whose stringent regulation is critical for maintaining HSC functionality. We will explore the interplay between replication and nucleolar stress, investigate the intrinsic and extrinsic mechanisms surrounding decreased ribosomal biogenesis and impaired proteostasis, and identify the cellular programs responsible for the onset of replication stress in old HSCs to design functional rejuvenation interventions. This work has exciting implications for elucidating the biology of HSC aging at molecular resolution and identifying actionable targets for promoting HSC functional longevity, a logical strategy for restoring blood and immune cell production in the elderly.

项目描述 血液系统老化的标志，如慢性炎症性疾病，贫血， 免疫衰老和血液系统恶性肿瘤大部分由造血干细胞（HSC）引起 功能障碍HSC功能的缺失与代谢失调有关， 自噬，表观遗传保真度的丧失，复制应激相关的基因组不稳定性，以及长期暴露于 老年骨髓（BM）微环境中的局部炎症。然而，这些仍然主要是 HSC老化的描述性特征。该项目旨在开发一个连贯且机械的模型来说明这些如何 外源性信号和内源性分子介质促进了老年HSC功能障碍，最终提示 振兴干预措施的可行目标。在目标1中，我们将测试自噬的假设， 参与是一种促生存的应激反应机制，可以保护一部分老年HSC免受慢性应激反应的影响 老年BM龛炎症。具体地说，我们将探讨老年人氧化代谢的增加是否会影响老年人的健康。 HSC的功能是补偿由于慢性炎症诱导的胰岛素引起的葡萄糖利用率降低 阻力越来越多的人认识到胰岛素抵抗会影响非典型组织，如大脑， 它与年龄相关的炎症和神经退化有关。我们将确定 炎症骨髓环境直接促进胰岛素/IGF-1途径抵抗，这如何驱动自噬 旧HSC子集的参与和代谢适应，以及旧HSC再生潜力是否可以 通过胰岛素敏感性和葡萄糖摄取正常化，通过禁食/再喂养干预改善。 在目标2中，我们将进一步剖析复制应激如何导致衰老HSC的功能衰竭。在 特别是，我们将重点放在脆弱的核糖体DNA（rDNA）基因座，这是严重影响复制 在老HSC中的应激，干扰核糖体生物合成。核糖体生物合成的缺陷导致了 游离核糖体蛋白触发激活p53依赖的核仁应激反应，以及缺陷 在蛋白质翻译中，其严格调节对于维持HSC功能至关重要。我们将探讨 复制和核仁应力之间的相互作用，研究周围的内在和外在机制 核糖体生物合成减少和蛋白质稳态受损，并确定负责的细胞程序 老年HSC中复制应激的开始，以设计功能性复壮干预措施。这项工作令人兴奋 在分子分辨率上阐明HSC衰老的生物学和确定可操作的靶点的意义 促进HSC功能寿命，这是一种恢复造血和免疫细胞产生的逻辑策略， 老人