Basic Aspects of Hematopoietic Stem Cells and Aging

造血干细胞和衰老的基本方面

• 批准号: 9433046
• 负责人: PETER J. QUESENBERRY
• 金额: $ 28.98万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9433046
• 关键词: Age; Aging; Alpha Cell; Attention; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Bromodeoxyuridine; Cell Aging; Cell Cycle; Cell physiology; Cells; Characteristics; Data; Development; Engraftment; Epitopes; FRAP1 gene; Family; Female; Functional disorder; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Immune system; Incidence; Individual; Investigation; Knowledge; Label; Lead; Marrow; Mus; Myelogenous; Phenotype; Population; Proliferating; Proto-Oncogene Protein c-kit; Reactive Oxygen Species; Regulation; Role; SLAM protein; Staining method; Stains; Stem cells; Suicide; Surface; System; Thymidine; Transplantation; Work; age effect; age related; aged; base; functional status; in vivo; male; mitochondrial metabolism; senescence; stem cell population; telomere

Project Summary: Changes in hematopoiesis and hematopoietic stem cells are an important component of aging. Many critical studies on the roles in hematopoietic aging of telomere dysfunction, cellular senescence and induction of the senescence-associated secretory phenotype, sitruin family effects, mitochondrial metabolism, the mechanistic target of rapamycin (mTOR), decline in the immune system and changes induced by a variety of toxic entities many of which involve Reactive Oxygen Species (ROS) were carried out employing highly purified hematopoietic stem cells. Studies on purified murine hematopoietic stem cells as exemplified by lineage negative c- kit+Sca-1+ (LSK) cells with or without CD150 marking, have indicated that with aging the number of phenotypically defined stem cells increases while the function of these cells decreases and myeloid skewing occurs. Much of the work on hematopoiesis in the aged has relied on studies of purified stem cells and is based on the assumption that these cells are non cycling or dormant. However, our work has shown that the long-term multi-lineage repopulating cell in lethally irradiated hosts is actively cycling and always changing. The key to these findings was the study of whole un-separated marrow stem cells with long-term multi-lineage engraftment as the assay. We feel that most studies to date on hematopoietic stem cells in aging have used purified stem cells, which are not representative of the true marrow stem cell populations. We propose here to study the content, cell cycle status and differentiation characteristics of un-separated marrow stem cells in young and aged mice and in male and female mice. We will separate cells into G0, G1 and S/G2/M fractions and evaluate engraftment. We will also utilize tritiated thymidine suicide to assess cycle status of stem cells in un- separated marrow and in vivo bromodeoxyuridine (BrdU) labeling to assess the flux of stem cells through cell cycle. These studies should give an important new base for further studies on the effects of aging on hematopoietic stem cells.

项目概要： 造血和造血干细胞的变化是衰老的重要组成部分。 许多关于端粒功能障碍、细胞衰老和造血功能障碍在造血衰老中的作用的重要研究， 衰老和衰老相关分泌表型的诱导，sitruin家族 影响，线粒体代谢，雷帕霉素的机制靶点（mTOR）， 免疫系统和各种有毒物质引起的变化，其中许多涉及 采用高纯度的造血干细胞， 细胞纯化小鼠造血干细胞的研究，以谱系阴性的c- kit+Sca-1+（LSK）细胞，有或没有CD 150标记，表明随着年龄的增长， 表型确定的干细胞数量增加，而这些细胞的功能 减少和骨髓偏斜发生。关于老年人造血的大部分工作 依赖于对纯化干细胞的研究，并基于这些细胞是非细胞性的假设。 循环或休眠。然而，我们的研究表明，长期的多谱系繁殖 细胞在致命的辐射主机是积极的循环和不断变化。这些发现的关键是 是研究完整的未分离的骨髓干细胞与长期的多谱系 移植作为测定。我们认为，迄今为止，大多数关于造血干细胞的研究， 衰老使用纯化的干细胞，这不是真正的骨髓干细胞的代表 人口。本文拟从蛋白质的含量、细胞周期状态及分化等方面进行研究 未分离的骨髓干细胞在年轻和老年小鼠和雄性小鼠中的特征， 雌性老鼠我们将细胞分离成G 0、G1和S/G2/M部分，并评价植入。 我们还将利用氚化胸苷自杀来评估非肿瘤干细胞的周期状态。 分离骨髓和体内溴脱氧尿苷（BrdU）标记以评估干细胞通量 通过细胞周期。这些研究将为进一步研究 衰老对造血干细胞的影响