Mechanism of action of uniquely human genes in the injury response

人类独特基因在损伤反应中的作用机制

• 批准号: 10623763
• 负责人: Todd W Costantini
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623763
• 关键词: Acute Lung Injury; Animal Model; Anti-Inflammatory Agents; Burn injury; Cells; Cessation of life; Clinical; Clinical Research; Development; Functional disorder; Gene Expression; Genes; Goals; Human; Immune; Immune response; Immune system; Inflammatory; Injury; Lung; Macrophage; Mediating; Modeling; Multiple Organ Failure; Mus; Organ; Patients; Phenotype; Research; Role; Sampling; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Therapeutic Effect; Transgenic Mice; Trauma; Variant; alpha-bungarotoxin receptor; cholinergic; gene function; genetic approach; induced pluripotent stem cell; injured; monocyte; novel; novel therapeutic intervention; pre-clinical research; programs; response; response to injury; severe burns; severe injury; systemic inflammatory response; therapeutic target; translational therapeutics

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.

项目摘要/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。尽管进行了数十年的研究， 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，人类特有的免疫系统差异对区分 人类对其他物种所观察到的伤害反应。这些物种特有的差异可能 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(UHGs)，其表达经常追溯到人类 免疫细胞可能解释了损伤后人类全身炎症反应综合征的一些差异。最重要的是 我的研究计划的目标是系统地定义区分人类免疫的因素 其他物种的反应，表征超高纯度物质对人类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 最近发现了人类特有的CHRFAM7A基因的一个新角色，它是 介导胆碱能抗炎的保守α7烟碱型乙酰胆碱受体(α7nAchR) 发信号。除了降低治疗药物针对α7nAchR的能力外，我们出人意料地 已证明人CHRFAM7A在转基因小鼠中的表达功能可导致 在严重烧伤模型中，增加单核细胞对肺的动员，减少急性肺损伤。 我们在MIRA方案中的研究重点是确定UHGs的功能和作用机制 它们在单核/巨噬细胞中高表达，并与损伤反应相关。至 演示UHG的功能相关性，我们将使用组合的精密动物模型， 人类诱导多能干细胞(IPS)的遗传学方法，以及来自创伤和 烧伤病人。在这项研究计划中，我们建议1)在动物身上测试细胞特异性UHG功能 严重损伤模型；2)建立人巨噬细胞iPS细胞系统；3) 确定UHGs如何改变以抗炎信号通路为靶点的疗法的效果； 以及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UHGs如何使人类对伤害的免疫反应独一无二可能会允许 用于开发旨在调节全身炎症反应综合征和减少器官的新型治疗干预措施 严重创伤和烧伤后的功能障碍。