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.

项目摘要： 干细胞在生物体的一生中通过它们的功能不断地补充组织和器官。 自我更新和分化的特殊能力。干细胞克隆寿命的延长导致了 细胞和分子损伤的累积。随着时间的推移， 引发了许多与年龄有关的问题。例如，B细胞和T细胞产生的年龄依赖性下降 起源于干细胞水平，是老年人免疫问题的原因。此外，本发明还提供了一种方法， 儿童的白血病主要涉及淋巴系，而老年人的白血病主要是髓系 在起源。这种差异与造血干细胞（HSC）的年龄依赖性变化有关。 在群体水平上从淋巴偏向性向髓样偏向性的分化。 最近已经清楚的是，单个HSC并不以相同的速度老化。我实验室的研究 其他人认为，在同一个生物体中，同样年龄的HSC表现出不同水平的髓样偏向性。的 单个HSC的克隆扩增也可以如此广泛地变化，以致于发现少数HSC克隆提供所需的造血干细胞。 整个血液池的老年人。这些观察结果表明，相同的单个干细胞 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解决单细胞水平的这个问题。我们 我收集的初步数据表明，个体HSC的不同衰老表型受到调控， 在克隆水平上。在这项研究中，我们将研究细胞和分子机制 这是个体HSC的异质老化表型的基础。我们的研究可能会发现新的衰老 在群体水平上检测不到的调节因素。 完成我们提出的研究将提供许多直接的临床效益。我们的发现将 促进对许多与年龄相关的血液和免疫疾病的发病机制的理解，包括 骨髓衰竭、骨髓增生性疾病和骨髓增生异常综合征。我们还可以发现新的 调节基因，以改善目前的治疗或开发新的类别的疗法来治疗这些疾病。我们 最终目标是利用个体干细胞差异老化的机制， 提高老年人的生活质量。