Mechanism of action of uniquely human genes in the injury response

项目概要/摘要 全身炎症反应损伤 (SIRS) 导致的多器官衰竭是主要原因 严重创伤和烧伤后的晚期并发症和死亡。尽管经过数十年的研究， 限制损伤后 SIRS 反应的治疗方法仍然是一个未得到满足的临床需求。新兴 研究指出，人类免疫系统的特异性差异使我们的免疫系统与众不同 与在其他物种中观察到的人类伤害反应不同。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却失败了 人体临床研究。独特的人类基因 (UHG)，其表达经常追踪人类 免疫细胞可能是受伤后人类 SIRS 中的一些差异的原因。首要的 我的研究计划的目标是系统地定义区分人类免疫的因素 来自其他物种的反应，描述 UHG 对人类 SIRS 的贡献，并了解如何 这些基因影响针对抗炎信号通路的治疗。为此，我们有 最近发现了独特的人类 CHRFAM7A 基因的新作用，该基因是 保守的 α7 烟碱乙酰胆碱受体 (α7nAchR)，介导胆碱能抗炎作用 发信号。除了降低治疗靶向 α7nAchR 的能力之外，出乎意料的是，我们 已经证明人类 CHRFAM7A 表达在转基因小鼠中发挥作用，导致 在严重烧伤模型中，增加单核细胞向肺部的动员并减少急性肺损伤。 我们在此 MIRA 提案中的研究重点是确定 UHG 的功能和作用机制 在单核细胞/巨噬细胞中高度表达并与损伤反应相关。至 证明 UHG 的功能相关性，我们将结合使用精密动物模型， 人类诱导多能干细胞 (iPS) 的遗传方法以及来自创伤和创伤的临床样本 烧伤患者。在本研究项目中，我们建议 1) 在动物中测试细胞特异性 UHG 功能 重伤模型； 2）开发用于人类巨噬细胞机制研究的iPS细胞系统； 3） 确定 UHG 如何改变针对抗炎信号通路的治疗效果； 4) 评估相对 UHG 表达如何改变单核细胞的炎症表型 受伤的病人。了解 UHG 如何使人类对伤害的免疫反应变得独特可能有助于 表彰其开发旨在调节 SIRS 和减少器官功能的新型治疗干预措施 严重外伤和烧伤后功能障碍。

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.