Mechanism of Immune Dysfunction and Morbid Outcomes in Response to Shock/Sepsis

响应休克/脓毒症的免疫功能障碍和病态结果的机制

• 批准号: 10173331
• 负责人: Alfred Ayala
• 金额: $ 56.14万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10173331
• 关键词: ATAC-seq; Accounting; Acute Lung Injury; Adoptive Transfer; Age; Animals; Anti-Inflammatory Agents; Apoptosis; Area; Automobile Driving; Cause of Death; Cell surface; Cells; Cessation of life; Clinical Research; Consensus; Cre-LoxP; Critical Illness; Defect; Developed Countries; Development; Endothelium; Epigenetic Process; Epithelial Cells; Etiology; Event; Family; Genetic; Hemorrhagic Shock; Hospitals; Immune; Immune System Diseases; Immune system; Immunoglobulin Domain; Immunologic Memory; Incidence; Injury; Intensive Care Units; Intestines; Leukocytes; Ligands; Liver; Lung; Lymphoid Cell; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Myelogenous; Outcome; Patients; Population; Prognostic Marker; Protein Family; Proteins; Reporting; Role; SARS-CoV-2 infection; Sepsis; Shock; Supportive care; Suppressor-Effector T-Lymphocytes; Surgical Intensive Care; Survivors; T-Cell Activation; T-Lymphocyte; base; bisulfite; cecal ligation puncture; comparative; design; epigenomics; immune function; inhibitor/antagonist; injured; kidney dysfunction; member; microbiota; mortality; mouse model; neonatal sepsis; neonate; novel; organ growth; organ injury; patient population; programs; protein expression; pyrosequencing; receptor; response; septic; single-cell RNA sequencing; therapeutic target; transcriptome sequencing; transcriptomics

Project Summary/Abstract At last count, sepsis was reported to be the leading cause of death in U.S hospital intensive care units (ICU); accounting for ~1 in 5 deaths world-wide; its incidence is anticipated to rise as the populations in developed countries age; and it was the consensus cause of death assigned to those dying from COVID-19 infection. Most frustrating, is that while we continue to optimize the supportive care for these critically ill patients, we have yet to see a novel molecular etiology-based therapy make a sustained impact on overall septic morbidity/ mortality. Excitingly, while working for years on defining numerous defects of components of both adaptive and innate immune responsiveness induced by shock and/or sepsis, we have uncovered novel role(s) for a number of the B7-family of cell-associated co-inhibitory receptors, Programmed Cell Death Receptor-1 [PD-1], B-/T- Lymphocyte Attenuator [BTLA], recently, V-domain Immunoglobulin Suppressor of T cell Activation [VISTA, a.k.a., B7-H5, PD-1H] and their respective cell surface ligands; popularly referred to as checkpoint proteins. In this competitive renewal of our MIRA program, we propose to continue to push forward the 3 project areas we brought together previously under the over-arching concept that by understanding the mechanism(s) of injury/shock and/or sepsis that serve to predispose animals (experimentally) or critically ill/injured patients to develop morbid outcomes, we can elucidate not only novel prognostic markers of patient’s course, but uncover unique therapeutic targets for their treatment. In the 1st Project area we will determine how the select expression of PD-1, BTLA or VISTA, on myeloid as opposed to lymphoid cells alters the development of morbid events associated with sepsis; then, how the expression of ligands for these co-inhibitory molecules, on leukocytes and/or endothelial/epithelial cells, contribute to the onset of septic liver, intestine and/or kidney dysfunction. In our 2nd Project area, we will utilize a novel murine model of indirect-acute lung injury (iALI)(dual insults of hemorrhage shock followed by cecal ligation & puncture [CLP]) to ask how checkpoint protein expression not only effect the patho-mechanisms driving the development of iALI, but how are these co- inhibitors alter cell ‘priming’/’innate immune memory’/function by following pulmonary immune/non-immune cell transcriptomic/epigenomic fate/programing. Finally, (3rd Project) since the neonate possesses a unique/naïve immune system and is more susceptible to morbid response in the face of infectious challenge; we ask how the expression of members of the B-7 family of proteins and/or their ligands not only have a comparative impact on the response to septic insult, but how this alters their microbiota and epigenetic makeup/immune function as survivors mature? To do this we will interrogate these 3 cogent models of sepsis, shock/sepsis and/or neonatal sepsis, by applying a combination genetic/Cre-Lox mouse models, adoptive transfer, single cell RNA-seq/ATAC- seq, 16S microbiota RNA-seq and bisulfite/pyrosequencing to examine these questions/hypotheses along with select observational clinical studies in the critical ill patient population.

项目概要/摘要 据最新统计，脓毒症是美国医院重症监护病房 (ICU) 的首要死因； 约占全世界死亡人数的五分之一；随着发达国家人口的增加，其发病率预计还会上升 国家老龄化；这是死于 COVID-19 感染者的共识原因。 令人沮丧的是，虽然我们继续优化这些危重患者的支持性护理，但我们尚未 看到一种基于分子病因学的新型疗法对脓毒症总体发病率/死亡率产生持续影响。 令人兴奋的是，多年来，我们致力于定义适应性和先天性组件的众多缺陷 休克和/或脓毒症引起的免疫反应，我们发现了许多新的作用 B7 细胞相关共抑制受体家族，程序性细胞死亡受体-1 [PD-1]，B-/T- 淋巴细胞衰减剂 [BTLA]，最近，T 细胞激活的 V 域免疫球蛋白抑制剂 [VISTA， 又名 B7-H5、PD-1H] 及其各自的细胞表面配体；通常称为检查点蛋白。 在 MIRA 计划的竞争性更新中，我们建议继续推进我们的 3 个项目领域 先前在总体概念下汇集在一起​​，即通过了解 伤害/休克和/或败血症，导致动物（实验性）或危重/受伤 如果患者出现病态结果，我们不仅可以阐明患者病情的新预后标志物 当然，但我们将在第一个项目领域确定其治疗的独特治疗目标。 PD-1、BTLA 或 VISTA 在骨髓细胞而不是淋巴细胞上的选择性表达如何改变 与脓毒症相关的病态事件的发展；然后，这些共抑制的配体的表达如何？ 白细胞和/或内皮/上皮细胞上的分子会导致脓毒症肝、肠和/或 在我们的第二个项目领域，我们将利用一种新型的间接急性肺损伤小鼠模型。 (iALI)（出血性休克的双重损伤，然后盲肠结扎和穿刺[CLP]）询问如何检查点 蛋白质表达不仅影响驱动 iALI 发展的病理机制，而且还影响这些因素如何共同作用。 抑制剂通过跟随肺部免疫/非免疫细胞来改变细胞“启动”/“先天免疫记忆”/功能 最后，（第三个项目）因为新生儿拥有独特的/天真的。 免疫系统在面对感染挑战时更容易产生病态反应； B-7 蛋白家族成员和/或其配体的表达不仅对 对脓毒症损伤的反应，但这如何改变他们的微生物群和表观遗传组成/免疫功能 为此，我们将询问这 3 种令人信服的脓毒症、休克/脓毒症和/或新生儿模型 脓毒症，通过应用组合遗传/Cre-Lox 小鼠模型、过继转移、单细胞 RNA-seq/ATAC- seq、16S 微生物组 RNA-seq 和亚硫酸氢盐/焦磷酸测序来检验这些问题/假设以及 选择危重病人群体中的观察性临床研究。