Aging-induced Alterations in the Microenvironment as Drivers of Myeloid Lineage Skewing

衰老引起的微环境变化是骨髓谱系偏斜的驱动因素

• 批准号: 9542466
• 负责人: Jennifer Jean Trowbridge
• 金额: $ 15万
• 依托单位: JACKSON LABORATORY
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9542466
• 关键词: ATAC-seq; Activities of Daily Living; Age; Age of Onset; Age-Months; Aging; Aging-Related Process; Automobile Driving; Biological; Blood; Bone Marrow; C57BL/6 Mouse; Cell Aging; Cell physiology; Cells; Complex; Data; Engraftment; Family; Flow Cytometry; Gene Expression Profiling; Health; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Homing; Human; Image; Immune; In Vitro; Incidence; Infection; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Knock-out; Lymphoid; Maintenance; Mediating; Molecular; Molecular Analysis; Mus; Myelogenous; Myeloid Leukemia; Natural regeneration; Patients; Phenotype; Population; Precision therapeutics; Process; Production; Public Health; Repression; Research; Resolution; Risk; Signal Transduction; Signaling Molecule; Specificity; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transplantation; Work; adaptive immunity; age related; aged; base; cell type; cost; design; effective intervention; functional decline; functional disability; in vivo; middle age; neutralizing antibody; prevent; regenerative; response; self-renewal; theories; therapy design; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The process of aging causes functional decline of the hematopoietic system, including reduced capacity for regeneration, increased risk of infections, and increased risk of certain forms of blood cancer. This is a significant health concern due to the worldwide increase in the age of the population and incidence of these age-related conditions. No intervention therapies currently exist to prevent functional decline of the hematopoietic system with aging, largely due to a lack of understanding of the cellular and molecular alterations that occur at the age of onset to cause functional hematopoietic decline. As hematopoietic stem cells assure long-term tissue maintenance, it is widely accepted based on experimental evidence that loss of proper hematopoietic stem cell function in the bone marrow during aging is a major cause of hematopoietic decline. Our preliminary data demonstrate that at the age of onset of functional hematopoietic decline, alterations in the bone marrow microenvironment are necessary and sufficient to cause hematopoietic stem cell aging, and identify reduced levels of the signaling molecule Insulin-like Growth Factor 1 (IGF-1) in the bone marrow as a candidate driver of hematopoietic stem cell aging. This project will use cellular and molecular biological approaches in aging mice to characterize the specific cellular and molecular alterations in the aging bone marrow microenvironment and how these cause functional decline of hematopoietic stem cells, including the specific cell type(s) responsible for reduced production of IGF-1 and how reduced IGF-1-mediated signaling drives functional decline of hematopoietic stem cells. Results of this project will reveal the mechanisms causing functional decline of the hematopoietic system with aging, and identify targeted, molecular- and cell type-specific therapeutic strategies to preserve regenerative capacity and immune cell function during aging.

项目总结/摘要 衰老的过程导致造血系统的功能下降，包括造血能力的降低。 再生，感染的风险增加，以及某些形式的血癌的风险增加。这是一 由于世界范围内人口年龄的增长和这些疾病的发病率， 与年龄有关的条件。目前还没有干预疗法来防止 造血系统随着衰老，很大程度上是由于缺乏对细胞和分子的了解， 在发病年龄发生的改变，导致造血功能下降。作为造血干细胞 细胞确保长期的组织维持，基于实验证据， 衰老过程中骨髓中适当的造血干细胞功能是造血干细胞缺乏的主要原因。 下降我们的初步数据表明，在造血功能下降的年龄开始， 骨髓微环境的改变是导致造血干细胞生成的必要且充分的条件 细胞老化，并确定骨中信号分子胰岛素样生长因子1（IGF-1）水平的降低 骨髓作为造血干细胞老化的候选驱动因素。这个项目将使用细胞和分子 衰老小鼠的生物学方法，以表征衰老过程中特定的细胞和分子变化 骨髓微环境以及这些微环境如何导致造血干细胞功能下降，包括 负责IGF-1产生减少的特定细胞类型以及减少的IGF-1介导的 信号传导驱动造血干细胞的功能衰退。该项目的结果将揭示 机制造成造血系统功能下降与老化，并确定有针对性的， 保护再生能力和免疫细胞的分子和细胞类型特异性治疗策略 在老化过程中发挥作用。