Mechanisms of Hematopoietic Stem Cell and Blood aging

项目说明 血液系统老化的特征，如慢性炎症性疾病，贫血， 免疫衰老和血液系统恶性肿瘤，很大程度上是由造血干细胞(HSC)引起的 功能障碍。与年龄相关的HSC功能丧失与代谢放松调节有关，增加对 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以及慢性暴露于 老年骨髓微环境中的局部炎症。然而，这些在很大程度上仍然 HSC老化的描述性特征。这个项目旨在开发一个连贯的和机械的模型，说明这些 外在信号和内在分子介质促进陈旧性HSC功能障碍，最终提示 返老还童干预的可操作目标。在目标1中，我们将检验自噬的假设 参与是一种生存的应激反应机制，它保护一部分旧的HSC免受慢性 老年骨髓壁龛的炎症反应。具体地说，我们将探讨老年人氧化代谢是否增强 HSCs对慢性炎症诱导的胰岛素引起的葡萄糖利用下降的补偿作用 抵抗。越来越多的人认识到，胰岛素抵抗会影响到非规范组织，如大脑， 它与年龄相关的炎症和神经退行性变有关。我们将确定如何 炎症的骨髓环境直接促进胰岛素/IGF-1途径抵抗，这是如何驱动自噬的 旧HSC子集的接合和代谢适应，以及旧HSC再生潜力是否可以 通过禁食/再喂养干预改善胰岛素敏感性和葡萄糖摄取正常化。 在目标2中，我们将进一步剖析复制应激如何导致衰老的HSCs的功能衰竭。在……里面 特别是，我们将关注脆弱的核糖体DNA(RDNA)基因座，这些基因座受到复制的严重影响 应激在老的肝星状细胞，干扰核糖体的生物发生。核糖体生物发生缺陷导致堆积 激活依赖于P53的核仁应激反应的游离核糖体蛋白以及缺陷 在蛋白质翻译中，其严格的调控对维持HSC的功能至关重要。我们将探索 复制和核仁应激之间的相互作用，研究周围的内在和外在机制 核糖体生物合成减少和蛋白稳定受损，并确定负责的细胞程序 老年造血干细胞复制应激的启动以设计功能性年轻化干预。这项工作有令人兴奋的地方 从分子水平阐明HSC衰老的生物学机制和确定可操作靶点的意义 对于促进HSC功能长寿，恢复血液和免疫细胞生产的合理策略 老年人。

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.