Dissecting the aging of hematopoietic stem cells by genetic tracing in vivo

通过体内基因追踪剖析造血干细胞的衰老

• 批准号: 8798183
• 负责人: Boris Reizis
• 金额: $ 21.44万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2015-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8798183
• 关键词: Aberrant DNA Methylation; Address; Age; Aging; Aging-Related Process; Animals; Blood; Blood Cells; Bone Marrow; Cell Aging; Cell Separation; Cell physiology; Chronic; Chronic stress; Clonal Expansion; Color; Complement; DNA; DNA Methylation; Defect; Dioxygenases; Elderly; Epigenetic Process; Genetic; Genetic Recombination; Goals; Hematopoiesis; Hematopoietic stem cells; Immune; Impairment; Inflammatory; Label; Life; Lymphocyte; Methods; Methyltransferase; Molecular; Monitor; Mouse Strains; Multiple Abnormalities; Mus; Mutation; Myelogenous; Myeloid Cells; Myeloproliferative disease; Organism; Pathway interactions; Pattern; Peripheral; Population; Production; Property; Regulation; Reporter; Risk; Role; Stem cells; Stimulus; System; Tamoxifen; Therapeutic; Time; Transgenes; Transgenic Mice; Transplantation; Work; base; cell age; cell type; demethylation; in vivo; insight; juvenile animal; leukemia; mutant; novel; novel strategies; prevent; public health relevance; self-renewal; stem cell differentiation; stem cell population

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) in the mammalian bone marrow (BM) continuously give rise to all blood cell types throughout the entire life. The HSC activity in aging is characterized by multiple abnormalities that prevent the replenishment of peripheral lymphocytes and greatly increase the risk of myeloproliferative disorders and leukemia. To understand precise mechanisms of age-associated HSC impairment, it is necessary to analyze the function of endogenous HSCs in intact aging organisms. This task has been elusive, as standard methods of HSC analysis rely on cell isolation and transfer into irradiated recipients. We have generated a system that allows specific labeling of endogenous HSCs and tracing of their progeny in intact mice. This novel system will be used to characterize the function of endogenous HSCs in aging, using three Specific Aims. In Aim 1, the self- renewal and differentiation of endogenous HSCs will be characterized in old versus young animals. In Aim 2, the clonal dynamics of HSC compartment during aging will be analyzed. In Aim 3, the role of DNA methylation regulators in the function of endogenous HSCs will be studied. Collectively, these studies would directly examine the properties of unmanipulated HSCs during aging, and clarify the mechanisms of aging-associated abnormalities of hematopoiesis.

描述（由申请人提供）：哺乳动物骨髓（BM）中的造血干细胞（hsc）在整个生命过程中不断产生所有类型的血细胞。衰老过程中HSC的活性表现为多种异常，这些异常阻止了外周血淋巴细胞的补充，大大增加了骨髓增生性疾病和白血病的风险。为了了解年龄相关的HSC损伤的确切机制，有必要分析内源性HSC在完整衰老生物体中的功能。这项任务一直难以捉摸，因为HSC分析的标准方法依赖于细胞分离和转移到辐照受体。我们已经建立了一个系统，可以对内源性造血干细胞进行特异性标记，并在完整的小鼠中追踪它们的后代。这个新系统将用于表征内源性hsc在衰老中的功能，使用三个特定目标。在目的1中，内源性造血干细胞的自我更新和分化将在老年动物和年轻动物中进行表征。在Aim 2中，将分析HSC细胞室在衰老过程中的克隆动力学。在Aim 3中，将研究DNA甲基化调节剂在内源性造血干细胞功能中的作用。总的来说，这些研究将直接检查未处理的造血干细胞在衰老过程中的特性，并阐明与衰老相关的造血异常的机制。