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: 9206168
• 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/9206168
• 关键词: 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; Economics; Elderly; Emergency Situation; Exhibits; Failure; Fracture; Functional disorder; Genetic Transcription; Genomics; Genotype; Healthcare; 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; Leukocytes; Literature; Measures; Morbidity - disease rate; Mortality Determinants; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myelopoiesis; NF-kappa B; Natural Immunity; Nuclear Grade; Nuclear Translocation; Operative Surgical Procedures; Outcome; Pancytopenia; Pathway interactions; Patients; Phagocytosis; Phase; Phenotype; Play; Pneumonia; Population; Predisposition; Primary Infection; Process; Reactive Oxygen Species; Research; Risk; Role; Sampling; Secondary to; Seminal; Side; Societies; Stem cells; Stimulus; Stress; Testing; Time; Translating; Trauma; Traumatic injury; Work; age effect; age group; aged; base; bone aging; care burden; cell age; cell type; clinical investigation; experimental study; granulocyte; in vivo; injured; innovation; killings; macrophage; mortality; mouse model; neutrophil; novel; novel therapeutics; older patient; p65; patient population; pre-clinical; protein complex; public health relevance; recombinase-mediated cassette exchange; reconstitution; repaired; response; secondary infection; self-renewal; success; transcriptome; 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.

 描述（由申请人提供）：高龄人群（大于 55 岁）创伤后发病率和死亡率显着增加。由于老年人口不断增加，对这种疾病过程的研究越来越重要，特别是随着我们社会的经济和医疗负担不断升级。尽管数十年来针对创伤的临床前和临床研究都有希望，但我们对这一实体及其影响在老年人中加剧的原因的理解仍然不完整，很少有疗法在任何患者群体中取得成功。最近，先天免疫的几个方面已被确定对年轻人的免疫反应至关重要，而这种反应在严重受伤和随后感染后的老年人中并不理想。具体来说，中性粒细胞在炎症后通过称为“紧急骨髓生成”的过程被替换。这种情况发生在严重损伤后，此时骨髓粒细胞储存迅速释放，导致干细胞沿着骨髓途径增殖和分化增加。骨髓细胞与干细胞的正确分化取决于核因子 kappa 的激活 B (NF+B)，一种蛋白质复合物，在应激刺激后部分控制 DNA 转录。一个 对炎症的适当紧急骨髓生成反应对于宿主的生存至关重要，但与年轻患者相比，老年人的这种反应似乎不足。具体来说，我们假设与衰老相关的骨髓增生异常改变了对创伤性损伤的紧急骨髓生成反应，导致骨髓细胞不适当的分化和成熟，使宿主容易受到随后的感染。我们进一步提出，这种紧急骨髓生成的失败是由于与年龄相关的、NFκB依赖性炎症途径的慢性激活，以及创伤后造血干细胞（LSK群体）未能以NFκB依赖性方式创建功能性骨髓细胞群体。使用一种新型的鼠失血性休克和损伤模型，我们将：（1）确定某些造血干细胞（HSC），特别是短期造血干细胞（ST-HSC），在老年人对创伤的反应中是否无法沿着骨髓途径正确扩张和分化，以及是否在老年人中观察到由此产生的功能失调的中性粒细胞群。 这些次优 ST-HSC 导致创伤后的老年人； (2) 确定严重损伤后老年 ST-HSC 功能的缺陷（与青少年对应物相比）是否是由慢性低度 NFκB 依赖性炎症状态以及随后创伤后未能适当激活 NFκB 依赖性通路引起的； (3) 确定与老年人严重创伤后相关的 HSC 衰老是否也是由于未能适当激活骨髓 HSC 中 NFκB 依赖性通路所致。这项工作提出，衰老创伤后感染的易感性增加至少部分是由于骨髓生成缺陷导致中性粒细胞基因型、表型和功能紊乱，无法控制感染。第三个具体目标是将我们的“实验室”动物工作转化为人类，这种创新方法可以确定对仍表现出可塑性的细胞类型进行干预的领域。