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.

项目摘要/摘要 最后，据报道，败血症是美国医院重症监护病房（ICU）的主要死亡原因。 全球5例死亡中的5分之一；随着发达的人口的发展，它的事件预计会上升 国家年龄；这是分配给Covid-19感染的人的共识原因。最多 令人沮丧的是，尽管我们继续优化这些重症患者的支持性护理，但我们尚未 请参阅一种基于分子病因的新型治疗对整体化粪池的发病率/死亡率产生持续的影响。 令人兴奋的是，在定义自适应和先天性的许多组成部分多年的工作中 电击和/或败血症引起的免疫反应能力，我们发现了许多新作用 B7与细胞相关的共同抑制受体，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细胞活化的V域免疫球蛋白抑制剂[Vista，Vista， 又称B7-H5，PD-1H]及其各自的细胞表面配体；通常称为检查点蛋白质。在 我们的MIRA计划的这种竞争性更新，我们建议继续推动我们的3个项目领域 以前以整理的概念一起购买，该概念是通过了解 受伤/冲击和/或败血症，可用于诱发动物（实验性）或重症/受伤 患者发展病态的结果，我们不仅可以阐明患者的新型预后标记 当然，但是发现其治疗的独特治疗靶标。在第一个项目区域，我们将确定 PD-1，BTLA或VISTA的选择表达如何在髓样中而不是淋巴样细胞改变 与败血症相关的病态事件的发展；然后，如何对这些共抑制性配体的表达 分子在白细胞和/或内皮/上皮细胞上，有助于败血性肝脏，肠和/或 肾功能障碍。在我们的第二个项目区域，我们将利用一种新型的间接急性肺损伤的鼠模型 （IALI）（出血冲击的双重侮辱，然后是盲肠结扎和穿刺[CLP]）询问检查点如何 蛋白质表达不仅影响驱动IALI发展的病情机制，而且这些是如何共同的 抑制剂通过跟随肺免疫/非免疫细胞来改变细胞“启动”/“先天免疫记忆”/功能 转录组/表观基因组命运/编程。最后，（第三个项目），因为新生儿拥有独特/幼稚的 免疫系统，面对传染性挑战时，更容易受到病态反应的影响；我们问 B-7蛋白质家族和/或其配体的表达不仅对 对化粪池损伤的反应，但是这如何改变其微生物群和表观遗传化妆/免疫功能 幸存者成熟？为此，我们将询问这三种败血症，休克/败血症和/或新生儿的模型 败血症，通过应用遗传/Cre-lox小鼠模型，自适应转移，单细胞RNA-seq/atac- SEQ，16S微生物群RNA-Seq和Bisulfite/pyrosequencing，以检查这些问题/假设以及 在重症患者人群中选择观察性临床研究。