Hematopoietic Stem Cell Dysfunction in the Elderly after Severe Injury

 描述(由申请人提供)：高龄(55岁以上)的人创伤后的发病率和死亡率显著增加。随着老年人口的增加，对这种疾病过程的研究变得越来越重要，特别是在我们社会的经济和医疗负担不断上升的情况下。尽管几十年来对创伤的临床前和临床研究很有希望，但我们对这一实体以及为什么它的影响在老年人中加剧的理解仍然不完整，几乎没有治疗方法在任何患者群体中显示出成功。最近，天然免疫的几个方面已经被确定对年轻人的免疫反应至关重要，而这种反应在严重创伤和随后的感染后的老年人中是次优的。具体地说，中性粒细胞在炎症后通过一种被称为“紧急骨髓生成”的过程被替换。这发生在严重损伤后，当骨髓粒细胞储存迅速释放，并增加干细胞增殖和分化沿髓系途径的结果。干细胞向髓系细胞的正确分化依赖于核因子-kappa的激活 B(核因子B)，一种在应激刺激后部分控制dna转录的蛋白质复合体。一个 适当的炎症应急造血反应对宿主的生存至关重要，但与年轻患者相比，老年人的反应似乎不够充分。具体地说，我们假设与衰老相关的骨髓发育不良改变了创伤损伤的紧急骨髓生成反应，导致髓系细胞不适当的分化和成熟，使宿主容易受到后续感染。我们进一步认为，这种紧急骨髓生成的失败是由于年龄相关的、依赖于NFB的炎症通路的慢性激活，以及创伤后造血干细胞(LSK群体)未能以依赖于NFB的方式产生有功能的髓系群体。使用一种新的小鼠失血性休克和创伤的小鼠多发伤(PT)模型，更好地概括了人类的情况，我们将：(1)确定某些造血干细胞(HSCs)，特别是短期HSCs，在老年人对创伤的反应中是否不能正确地沿着髓系途径扩张和分化，以及，如果创伤后老年人出现的中性粒细胞功能障碍是由这些次优的ST-HSCs引起的；(2)确定与青少年相比，严重创伤后老年ST-HSC功能缺陷是否由创伤后慢性低级别NFB依赖的炎症状态以及随后未能适当激活NFB依赖的途径引起；以及(3)确定与严重创伤后老年人相关的HSC衰老是否也是由于未能适当激活骨髓HSC中的NFB依赖的途径所致。这项工作提出，老年创伤后感染易感性的增加，至少部分是由于骨髓生成缺陷导致的基因、表型和功能错乱的PMN无法控制感染。第三个具体目标将把我们的‘板凳边’动物工作转移到人类身上，这种创新的方法可以确定仍然表现出可塑性的细胞类型的干预领域。

 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.