Mechanism of action of uniquely human genes in the injury response

项目总结/摘要 全身性炎症反应（SIRS）导致的多器官功能衰竭是其主要原因 严重创伤和烧伤后的晚期并发症和死亡。尽管经过几十年的研究， 限制损伤后SIRS反应的治疗仍然是未满足的临床需求。新兴 研究指出，我们的免疫系统中人类特异性差异的贡献， 人类受伤后的反应与其他物种不同。这些物种特异性差异可能 解释为什么在用于临床前研究的动物模型中广泛成功的疗法在 人类临床研究。独特的人类基因（UHG），其表达经常跟踪人类 免疫细胞，可能解释了损伤后人类SIRS中的一些差异。总体 我的研究计划的目标是系统地定义区分人类免疫系统的因素。 从其他物种的反应，表征UHG对人类SIRS的贡献，并了解如何 这些基因影响靶向抗炎信号通路的治疗。为此我们 最近发现了一个新的作用，独特的人类CHRFAM 7A基因，是一个变异的， 保守的α7烟碱乙酰胆碱受体（α 7 nAchR），介导胆碱能抗炎 发信号。除了降低治疗剂靶向α 7 nAchR的能力外，出乎意料的是，我们 已经证明人CHRFAM 7A表达在转基因小鼠中起作用， 在严重烧伤模型中增加单核细胞向肺的动员并减少急性肺损伤。 我们在MIRA提案中的研究重点是确定UHGs的功能和作用机制 其在单核细胞/巨噬细胞中高度表达并与损伤反应相关。到 为了证明UHG的功能相关性，我们将使用精确的动物模型， 人类诱导多能干细胞（iPS）的遗传方法，以及来自创伤和 烧伤病人在这项研究计划中，我们建议1）测试细胞特异性UHG功能的动物 严重损伤模型; 2）开发iPS细胞系统用于人巨噬细胞中的机制研究; 3） 确定UHG如何改变靶向抗炎信号通路的治疗剂的效果; 和4）评估相对UHG表达如何改变单核细胞的炎性表型， 受伤的病人。了解UHG如何使人类对损伤的免疫反应独特， 用于开发旨在调节SIRS和减少器官损伤的新型治疗干预措施， 严重创伤和烧伤后的功能障碍。

PROJECT SUMMARY/ABSTRACT Multi-organ failure as a result of the systemic inflammatory response to injury (SIRS) is the leading cause of late complications and death after severe trauma and burn injury. Despite decades of research, therapeutics that limit the SIRS response following injury remains an unmet clinical need. Emerging research points to the contribution of human-specific differences in our immune system that distinguish the human injury response from that observed in other species. These species-specific differences may explain why therapies that are widely successful in animal models used for preclinical research fail in human clinical studies. Uniquely human genes (UHGs), with expression that frequently tracks to human immune cells, may account for some of these differences in human SIRS after injury. The overarching goal of my research program is to systematically define factors that distinguish the human immune response from other species, characterize the contribution of UHGs to human SIRS, and understand how these genes effect therapeutics that target anti-inflammatory signaling pathways. To this end, we have recently discovered a novel role for the uniquely human CHRFAM7A gene that is a variant of the conserved α7 nicotinic acetylcholine receptor (α7nAchR) that mediates cholinergic anti-inflammatory signaling. In addition to decreasing the ability of therapeutics to target the α7nAchR, unexpectedly, we have demonstrated that human CHRFAM7A expression functions in transgenic mouse mice to cause increased monocyte mobilization to lung and decreased acute lung injury in a model of severe burn injury. Our research focus in this MIRA proposal is to identify the function and mechanism of action of UHGs that are highly expressed in monocytes/macrophages and relevant in the injury response. To demonstrate the functional relevance of UHGs, we will use a combination of precision animal models, genetic approaches in human induced pluripotent stem (iPS) cells, and clinical samples from trauma and burn patients. In this research program, we propose to 1) test cell-specific UHG function in an animal model of severe injury; 2) develop an iPS cell system for mechanistic studies in human macrophages; 3) determine how UHGs alter the effect of therapeutics that target anti-inflammatory signaling pathways; and 4) evaluate how relative UHG expression alters the inflammatory phenotype of monocytes from injured patients. Understanding how UHGs make the human immune response to injury unique may allow for the development of novel therapeutic interventions aimed at modulating SIRS and decreasing organ dysfunction after severe trauma and burn.