Investigating the heterogeneous aging of individual hematopoietic stem cell clones

研究个体造血干细胞克隆的异质老化

• 批准号: 9769848
• 负责人: Rong Lu
• 金额: $ 51.9万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769848
• 关键词: Address; Age; Aging; Award; B-Lymphocytes; Blood; Calendar; Candidate Disease Gene; Cell Aging; Cells; Characteristics; Childhood Leukemia; Clinical; Clonal Expansion; Clonal Hematopoietic Stem Cell; Clone Cells; Data; Disease; Dysmyelopoietic Syndromes; Elderly; Exhibits; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Hematological Disease; Hematology; Hematopoietic Stem Cell heterogeneity; Hematopoietic stem cells; Human; Immune; Immune System Diseases; Incidence; Individual; Link; Longevity; Lymphoid; Lymphoid Cell; Lymphopoiesis; Molecular; Monitor; Mus; Myelogenous; Myeloproliferative disease; Organ; Organism; Pancytopenia; Pathogenesis; Phenotype; Population; Production; Quality of life; Regulator Genes; Rejuvenation; Research; Stem cells; System; T-Lymphocyte; Technology; Testing; Time; Tissues; Transplantation; age related; aged; base; cell behavior; differential expression; droplet sequencing; experimental study; hematopoietic stem cell self-renewal; improved; in vivo; innovation; leukemia; new technology; novel; older patient; response; self-renewal; single-cell RNA sequencing; stem cell differentiation; therapeutic target; tool

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.

项目概要： 干细胞在生物体的一生中不断补充组织和器官 自我更新和分化的特殊能力。干细胞克隆的寿命延长导致 细胞和分子损伤的积累。随着时间的推移，干细胞的功能发生变化 是许多与年龄有关的问题的根源。例如，B 细胞和 T 细胞产量随年龄而下降 起源于干细胞水平，导致老年人的免疫问题。此外， 儿童白血病主要涉及淋巴系，而老年人白血病主要涉及骨髓系 在原点。这种差异与造血干细胞 (HSC) 的年龄依赖性变化相关 在群体水平上从淋巴偏向到骨髓偏向的分化。 最近已经清楚的是，各个造血干细胞的衰老速度并不相同。我的实验室的研究和 其他人则认为，相同年龄的造血干细胞在单一生物体内表现出不同程度的骨髓偏向。这 各个 HSC 的克隆扩增差异也很大，以至于发现少数 HSC 克隆可以提供 老年人的整个血库。这些观察表明，相同的个体干细胞 同一生物体内的日历年龄获得不同的衰老表型。拟议的研究旨在 确定 HSC 衰老表型异质性的潜在机制。 我们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 已收集初步数据表明个体 HSC 的独特衰老表型受到调节 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 个体 HSC 的异质衰老表型的潜在原因。我们的研究可能会发现新的衰老 在人群水平上无法检测到的监管因素。 完成我们提出的研究将带来许多直接的临床益处。我们的研究结果将 促进对许多与年龄相关的血液和免疫疾病发病机制的了解，包括 骨髓衰竭、骨髓增生性疾病和骨髓增生异常综合征。我们还可能发现新的 改善当前疗法或开发治疗这些疾病的新型疗法的调节基因。我们的 最终目标是利用个体干细胞差异衰老的机制 提高老年人的生活质量。