Hematopoietic Stem Cell Dysfunction in the Elderly after Severe Injury

老年人严重受伤后造血干细胞功能障碍

• 批准号: 8859563
• 负责人: Philip A Efron
• 金额: $ 30万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-05 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8859563
• 关键词: 2 year old; Adolescent; Age; Aging; Animals; Area; Bacteria; Bone Marrow; Cell Aging; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Chemotaxis; Chronic; Complex; DNA; Data; Defect; Development; Disease; Dysmyelopoietic Syndromes; Elderly; Emergency Situation; Exhibits; Failure; Fracture; Functional disorder; Gene Expression Profile; Genetic Transcription; Genomics; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhagic Shock; Human; ITGAM gene; Immune; Immune response; Individual; Infection; Infection Control; Inflammation; Inflammatory; Injury; Intervention; Knock-out; Laboratories; Lead; Left; Leukocytes; Literature; Measures; Modeling; Morbidity - disease rate; Mortality Determinants; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; NF-kappa B; Natural Immunity; Nuclear Translocation; Operative Surgical Procedures; Outcome; Pancytopenia; Pathway interactions; Patients; Phagocytosis; Phase; Phenotype; Play; Pneumonia; Population; Predisposition; Process; Reactive Oxygen Species; Research; Risk; Role; Sampling; Secondary to; Seminal; Side; Societies; Stem cells; Stimulus; Stress; System; Testing; Time; Translating; Trauma; Work; age effect; age group; aged; base; care burden; cell type; clinical investigation; granulocyte; health economics; in vivo; injured; innovation; killings; macrophage; mortality; neutrophil; novel; older patient; p65; patient population; pre-clinical; protein complex; public health relevance; reconstitution; repaired; research study; response; secondary infection; self-renewal; success; transcriptomics; young adult

 DESCRIPTION (provided by applicant): People of advanced age (greater than 55 years old) have significantly increased morbidity and mortality after trauma. Since the elderly population is expanding, research into this disease process is increasingly relevant, especially with the escalating economic and health care burdens on our society. Despite decades of promising preclinical and clinical investigations in trauma, our understanding of this entity and why its effects are exacerbated in the elderly remains incomplete, with few therapies demonstrating success in any patient population. Recently, several aspects of innate immunity have been determined to be of vital importance to the young adult immune response, and this response is suboptimal in the aged after severe injury and subsequent infections. Specifically, neutrophils are replaced after inflammation through a process known as 'emergency myelopoiesis.' This occurs after severe injury when bone marrow granulocyte stores are rapidly released, and increased stem cell proliferation and differentiation along myeloid pathways results. Proper differentiation of myeloid cells from stem cells is dependent on activation of nuclear factor kappa B (NFB), a protein complex that partially controls DNA transcription after stressful stimuli. An appropriate emergency myelopoietic response to inflammation is essential to host survival but appears to be inadequate in the elderly as compared to younger patients. Specifically, we hypothesize that the myelodysplasia associated with aging modifies the emergency myelopoietic response to traumatic injury, resulting in inappropriate differentiation and maturation of myeloid cells, leaving the host susceptible to subsequent infection. We further propose that this failure of emergency myelopoiesis is due to age-associated, chronic activation of NFB-dependent inflammatory pathways, and a failure of hematopoietic stems cells (LSK populations) after trauma to create functional myeloid populations in a NFB-dependent manner. Using a novel murine polytrauma (PT) model of murine hemorrhagic shock and injury that better recapitulates the human condition, we will: (1) determine if certain hematopoietic stem cells (HSCs), specifically short term-HSCs (ST-HSCs), fail to properly expand and differentiate along myeloid pathways in the elderly response to trauma, and, if the resultant dysfunctional neutrophil population seen in the elderly after trauma results from these suboptimal ST-HSCs; (2) determine if the defects in aged ST-HSC function after severe injury, as compared to their juvenile counterparts, are caused by a chronic low-grade NFB-dependent inflammatory state and a subsequent failure to appropriately activate NFB-dependent pathways after trauma; and, (3) determine if the HSC senescence associated with elderly humans after severe trauma is also due to a failure to appropriately activate NFB-dependent pathways in bone marrow HSCs. This work proposes that increased susceptibility to infection after trauma in aging is due, at least in part, to defects in myelopoiesis that lead to genotypically, phenotypically and functionally deranged PMNs that fail to control infection. The third specific aim will translate our 'bench side' animal work to humans and this innovative approach could identify areas for intervention in cell types that are still exhibit plasticity.