Hematopoietic Stem Cell Dysfunction in the Elderly after Severe Injury

 描述（由申请人提供）：老年人（大于55岁）在创伤后的发病率和死亡率显著增加。由于老年人口正在扩大，对这种疾病过程的研究越来越重要，特别是随着我们社会经济和卫生保健负担的不断增加。尽管几十年来在创伤方面进行了有希望的临床前和临床研究，但我们对这种实体的理解以及为什么它的影响在老年人中加剧仍然不完整，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为对年轻成人免疫应答至关重要，并且这种应答在严重损伤和随后的感染后的老年人中是次优的。具体来说，中性粒细胞在炎症后通过一个称为“紧急骨髓生成”的过程被取代。“这发生在严重损伤后，当骨髓粒细胞储存迅速释放，干细胞增殖和分化增加沿着骨髓途径的结果。”干细胞向髓样细胞的正确分化依赖于核因子κ的激活 B（NF κ B B），一种在应激刺激后部分控制DNA转录的蛋白质复合物。一个 对炎症的适当的紧急骨髓生成反应对于宿主存活是必要的，但与年轻患者相比，老年患者的反应似乎不足。具体而言，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，导致骨髓细胞的不适当分化和成熟，使宿主易受随后的感染。我们进一步提出，这种紧急骨髓生成的失败是由于年龄相关的，NF-κ B依赖性炎症通路的慢性激活，以及创伤后造血干细胞（LSK群体）以NF-κ B依赖性方式产生功能性骨髓群体的失败。使用一种新的鼠出血性休克和损伤的鼠多发性创伤（PT）模型，该模型更好地再现了人类状况，我们将：（1）确定某些造血干细胞（HSC），特别是短期-HSC（ST-HSC），在老年人对创伤的反应中是否不能沿着骨髓途径适当地扩增和分化，以及，如果在老年人创伤后看到的功能失调的中性粒细胞群是由这些次优的ST-HSC引起的;（2）确定老年ST-HSC在严重损伤后的功能缺陷是否与其青少年对应物相比，由慢性低度NF-κ B依赖性炎症状态和创伤后随后未能适当激活NF-κ B依赖性通路引起;以及（3）确定与严重创伤后的老年人相关的HSC衰老是否也是由于未能适当激活骨髓HSC中的NF-κ B依赖性途径。这项工作提出，增加感染的易感性创伤后，在老化是由于，至少部分是由于骨髓细胞的缺陷，导致基因型，表型和功能紊乱的中性粒细胞，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，这种创新方法可以识别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.