Hematopoietic Stem Cell Senescence

造血干细胞衰老

• 批准号: 7862098
• 负责人: Jose Alberola-Ila
• 金额: $ 40.75万
• 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/7862098
• 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（由申请人提供）：老化小鼠中的造血干细胞（HSC）优先失去再生适应性免疫系统的能力。这种偏向于产生髓样细胞和其他HSC异常的偏斜可能导致人类看到的免疫衰老。也就是说，在老年人中，对疫苗接种的反应质量可能很差或不合适。引起这些变化和潜在机制的情况在很大程度上是未知的。虽然HSC受到化学疗法，放射线，DNA修复缺陷，端粒酶丧失和细胞因子升高的伤害，但在这种情况下，尚未报告性损失淋巴细胞的损失。相比之下，我们发现从反复暴露于非常低剂量的脂多糖的小鼠中恢复的HSC中的HSC中，髓样偏斜，有缺陷的自我更新和其他与年龄相关的变化。尽管事实是动物的健康状况总体良好，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变化可能是由内源性收费受体（TLR）配体与组织损伤和肥胖相关的。现在，我们将确定其他TLR配体以及炎症性肠病（IBD）动物模型是否发生这种现象。此外，我们将探索HSC受到伤害的手段。这些发现有望了解正常衰老以及许多慢性病，例如HIV/艾滋病，可能会加速免疫衰老。同样，可以发现与年龄相关的某些造血恶性肿瘤模式的转变。 公共卫生相关性：我们的免疫系统在老年时的效果降低了，有新的证据表明，这可能是由于低级感染的史而导致的。更多的研究可以揭示如何阻止甚至扭转衰老的这些后果。