Mechanisms of Immune Dysfunction after Trauma and Surgical Sepsis

项目摘要/摘要 创伤和外科脓毒症是全世界发病率和死亡率的主要原因之一。这两个都是急性的 侮辱可能导致免疫功能障碍，然后导致持续的危重疾病状态。这种免疫力 功能障碍表现为过度的全身炎症反应，可导致器官功能障碍； 同时抑制免疫防御，使患者容易受到继发感染。 然而，我们缺乏关于人类如何应对严重伤害的全面和综合的观点，以及更多 重要的是，这些反应在快速康复的患者和死亡和/或死亡的患者之间有何不同 持续发展的危重病。单细胞多重组学和血液分析的研究进展 平台，多重组学现在使表征跨越广泛的细胞状态和 在循环的生物分子景观中的模式深入到很深。在上一个融资周期中，我们 第一个对来自中国的血液样本进行单细胞基因组学和大规模多平台、多组学 伤势严重的病人。这项已发表的工作确定了许多新的发现，包括早期的大规模 将细胞成分释放到创伤患者的循环中，这些患者要么经历复杂的过程，要么死亡。 此外，对PBMC的开放染色质分析发现，仍处于危重状态的患者也有全身性 表观遗传学变化在早期免疫细胞类型中很明显，代表着多梳靶的抑制。在……里面 在一项研究中，我们将反向翻译这些和其他新发现来自我们最初的人类 对失血性休克和创伤小鼠模型的多组学分析以寻求潜在的治疗方法 目标。在另一项研究中，我们将扩展我们对多组数据的分析，以创建一份血液图谱 人类创伤反应。这个在线资源将包含关于循环免疫细胞范围的数据 严重损伤后常见的状态，并将这些与高维度的纵向变化相结合 循环蛋白质、脂质和其他代谢物的数据集。我们将应用最先进的计算技术 根据结果、治疗方法、年龄分层确定生物标记物和治疗靶点的策略 还有性爱。我们将把我们的结果与在脓毒症中发表的类似研究进行比较。除了这些发现和 我们的分析将产生机械性的见解，我们希望我们提供的资源将促进比较 对我们的数据集进行研究和进一步分析。

Project Summary/Abstract Trauma and Surgical Sepsis are among the leading causes of morbidity and death worldwide. Both of these acute insults can lead to immune dysfunction that then contributes to a state of persistent critical illness. This immune dysfunction is manifested by an excessive systemic inflammatory response that can lead to organ dysfunction; and a simultaneous suppression of immune defenses that renders patients susceptible to secondary infections. However, we lack a comprehensive and integrated view of how humans respond to severe injury, and more importantly, how these responses differ between patients that recover quickly vs. those that die and/or development persistent critical illness. Advances in single cell multiomics and blood analysis using multi- platform, multiomics now makes it possible to characterize changes across a broad range of cell states and patterns within the circulating biomolecule landscape to great depth. In the previous funding cycle, we were the first to perform single cell genomics and large-scale multi-platform, multiomics on blood samples from severely injured patients. This published work identified many novel findings, including the early massive release of cellular constituents into the circulation of trauma patients that follow a complicated course or die. In addition, open chromatin analysis of PBMC found that patients who remain critically ill also have global epigenetic changes evident early across immune cell types, representing de-repression of polycomb targets. In one line of research, we will reverse translate the these and other novel findings from our initial human multiomic analyses into our mouse model of hemorrhagic shock and trauma to pursue potential therapeutic targets. In another line of research, we will extend our analysis of multiomic data to create a Blood Atlas of the human trauma response. This online resource will incorporate data on the range of circulating immune cell states commonly seen after severe injury and integrate these with the longitudinal changes in high dimensional datasets of circulating proteins, lipids and other metabolites. We will apply state-of-the-art computational strategies to identify biomarkers and therapeutic targets with patients stratified by outcomes, treatments, age and sex. We will compare our results with similar published studies in sepsis. In addition to the discoveries and mechanistic insights our analysis will yield, we hope that the resources we provide will stimulate comparative studies and further analyses of our datasets.