Hematopoietic Stem Cell Senescence

造血干细胞衰老

• 批准号: 8269672
• 负责人: Jose Alberola-Ila
• 金额: $ 40.34万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269672
• 关键词: AIDS/HIV problem; Affect; Age; Aging; Aging-Related Process; Animal Model; Animals; Binding; Biochemical; Biological Markers; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Aging; Cell Count; Cell physiology; Cells; Characteristics; Chimera organism; Chronic; DNA Repair; Defect; Dose; Epigenetic Process; Exposure to; Flow Cytometry; Gene Expression Profile; Goals; Health; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Homing; Human; Immune system; Immunity; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Investigation; Learning; Ligands; Link; Lipopolysaccharides; Mus; Myelogenous; Myeloid Cells; Natural regeneration; Obesity; Pattern; Production; Radiation; Recording of previous events; Reporting; Research; Series; Signal Pathway; Stem cells; TLR4 gene; Telomerase; Testing; Tissues; Toll-like receptors; Transplantation; Vaccination; age related; aged; base; cell injury; cell type; chemotherapy; clinically relevant; cytokine; immunosenescence; normal aging; pathogen; progenitor; public health relevance; research study; response; self-renewal; senescence; stem

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSC) in aging mice preferentially lose the ability to regenerate the adaptive immune system. This skewing towards production of myeloid cells and other HSC abnormalities may contribute to the immunosenescence seen in humans. That is, the quality of responses to vaccination can be poor or inappropriate in aged individuals. The circumstances that elicit these changes and the underlying mechanisms are largely unknown. While HSC are harmed by chemotherapy, radiation, DNA repair defects, loss of telomerase and elevated cytokines, selective loss of lymphopoietic potential has not been reported in those circumstances. In contrast, we have found myeloid skewing, defective self-renewal and other age-related changes in HSC recovered from mice repeatedly exposed to very low doses of lipopolysaccharide. This is despite the fact that the animals were in generally good health and numbers of HSC were normal. These remarkable findings suggest that persistent low-grade infections and associated pathogen products might cause HSC senescence and ultimately compromise immunity. It is possible that similar HSC changes are caused by endogenous Toll- like receptor (TLR) ligands associated with tissue damage and obesity. We will now determine if the phenomenon occurs with other TLR ligands and in an animal model of inflammatory bowel disease (IBD). Additionally, we will explore the means through which HSC are harmed. The findings are expected to be informative about normal aging as well as many chronic conditions such as HIV/AIDS that may accelerate immunosenescence. Also, a basis may be found for age-related shifts in patterns of some hematopoietic malignancies. PUBLIC HEALTH RELEVANCE: Our immune systems become less effective in old age, and there is new evidence to suggest this can result from a history of low-grade infections. More study could reveal how to block or even reverse these consequences of aging.

描述（申请人提供）：衰老小鼠中的造血干细胞（HSC）优先丧失再生适应性免疫系统的能力。这种骨髓细胞产生和其他造血干细胞异常的倾向可能导致人类出现免疫衰老。也就是说，老年人对疫苗接种的反应质量可能较差或不适当。引发这些变化的环境和潜在机制在很大程度上尚不清楚。虽然 HSC 受到化疗、放疗、DNA 修复缺陷、端粒酶缺失和细胞因子升高的损害，但尚未有在这些情况下选择性丧失淋巴细胞生成潜力的报道。相比之下，我们发现反复暴露于极低剂量脂多糖的小鼠中恢复的 HSC 出现了骨髓偏斜、自我更新缺陷和其他与年龄相关的变化。尽管事实上这些动物总体健康状况良好并且HSC数量正常。这些显着的发现表明，持续的低度感染和相关的病原体产物可能会导致 HSC 衰老并最终损害免疫力。类似的 HSC 变化可能是由与组织损伤和肥胖相关的内源性 Toll 样受体 (TLR) 配体引起的。我们现在将确定这种现象是否发生在其他 TLR 配体以及炎症性肠病 (IBD) 动物模型中。此外，我们将探讨 HSC 受到损害的方式。预计这些发现将为正常衰老以及许多慢性疾病（例如可能加速免疫衰老的艾滋病毒/艾滋病）提供信息。此外，还可能为某些造血系统恶性肿瘤的模式与年龄相关的变化找到基础。 公共卫生相关性：我们的免疫系统在老年时变得不那么有效，有新的证据表明这可能是由低度感染史造成的。更多的研究可以揭示如何阻止甚至逆转衰老的这些后果。