Investigating the heterogeneous aging of individual hematopoietic stem cell clones

项目总结： 干细胞在生物体的一生中不断补充组织和器官，通过它们的 具有自我更新和差异化的特殊能力。干细胞克隆的延长寿命导致 细胞和分子损伤的累积。随着时间的推移，干细胞的功能发生了变化 这是许多与年龄有关的问题的基础。例如，B细胞和T细胞产量随年龄增长而下降 起源于干细胞水平，并对老年人的免疫问题负责。此外, 儿童白血病主要涉及淋巴系，而老年人白血病主要是髓系白血病。 在起源上。这种差异与造血干细胞(HSC)的年龄相关性变化有关。 在人群水平上从淋巴系偏向到髓系偏向的分化。 最近发现，单个造血干细胞的衰老速度并不相同。来自我实验室的研究和 其他人则认为，相同年龄的造血干细胞在单个生物体内表现出不同程度的髓系偏向。这个 单个HSC的克隆性扩增也可能差异很大，以至于发现一些HSC克隆提供了 老年人的整个血池。这些观察表明，相同的单个干细胞 同一生物体内的日历年龄具有不同的老化表型。这项拟议的研究旨在 确定HSC老化表型异质性的潜在机制。 我们已经开发了一套尖端工具来在单细胞水平上解决这个问题。我们 已经收集了初步数据，表明单个HSC的不同衰老表型受到调控 在克隆水平上。在拟议的研究中，我们将研究细胞和分子机制。 单个造血干细胞的异质性衰老表型的基础。我们的研究可能会发现新的衰老 在人口层面上无法检测到的监管因素。 我们建议的研究的完成将提供许多直接的临床益处。我们的发现将 促进对许多与年龄有关的血液和免疫疾病的发病机制的了解，包括 骨髓衰竭、骨髓增生性疾病和骨髓增生异常综合征。我们还可以确定新的 改善当前治疗方法或开发新的治疗方法来治疗这些疾病的调节基因。我们的 最终目标是利用个体干细胞不同老化的机制来 提高老年人的生活质量。

Project Summary: Stem cells continuously replenish tissues and organs over the lifetime of an organism through their special capacity for self-renewal and differentiation. The prolonged life span of stem cell clones results in the accumulation of cellular and molecular damage. The resulting functional changes to stem cells over time underlie many age-related problems. For example, age-dependent decline in B- and T-cell production originates at the stem cell level and is responsible for immune problems among the elderly. In addition, leukemia in children predominantly involves lymphoid lineages, while leukemia in the elderly is largely myeloid in origin. This difference correlates with age-dependent changes in hematopoietic stem cell (HSC) differentiation from lymphoid bias to myeloid bias at the population level. It has recently become clear that individual HSCs do not age at the same rate. Studies from my lab and others suggest that equally aged HSCs exhibit different levels of myeloid bias within a single organism. The clonal expansion of individual HSCs can also vary so widely that a few HSC clones are found to supply the entire blood pool of elderly individuals. These observations indicate that individual stem cells of the same calendar age within the same organism acquire different aging phenotypes. The proposed research aims to determine the mechanisms underlying the heterogeneity of HSC aging phenotypes. We have developed a suite of cutting-edge tools to address this question at the single cell level. We have collected preliminary data suggesting that the distinct aging phenotypes of individual HSCs are regulated at the clonal level. In the proposed research, we will investigate the cellular and molecular mechanisms underlying the heterogeneous aging phenotypes of individual HSCs. Our research may identify new aging regulatory factors that are undetectable at the population level. Completion of our proposed research will provide many immediate clinical benefits. Our findings will advance the understanding of the pathogenesis of many age-related blood and immune diseases, including bone marrow failure, myeloproliferative disorders, and myelodysplastic syndromes. We may also identify new regulatory genes that improve current therapy or develop new classes of therapies to treat these diseases. Our ultimate goal is to harness the mechanisms that underlie the differential aging of individual stem cells to improve quality of life for the elderly.