Role of ASC in TBI-Mediated Systemic Inflammation.

ASC 在 TBI 介导的全身炎症中的作用。

• 批准号: 10319965
• 负责人: JUAN Pablo DE RIVERO VACCARI
• 金额: $ 37.19万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319965
• 关键词: Acute; Affect; Age; Animals; Apoptosis; Appearance; Back; Behavior; Biological Assay; Blood Circulation; Brain; Brain Injuries; CASP1 gene; Cardiovascular system; Caspase; Cause of Death; Cell Death; Cells; Clinic; Control Animal; Data; Deposition; Development; Exhibits; Extracellular Space; Flow Cytometry; Functional disorder; Goals; Hematology; Histologic; Hour; Human; Immune; Immune signaling; Immunohistochemistry; Immunologics; Infiltration; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interleukin-1 beta; Leukocytes; Liquid substance; Lung; Lymphocyte; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mus; Natural Immunity; Neuraxis; Neurodegenerative Disorders; Neutrophil Infiltration; Organ; Outcome; Pathogenesis; Patients; Pattern; Peripheral; Persons; Play; Proteins; Reaction; Reactive Oxygen Species; Recovery of Function; Research; Role; Serum; Severities; Signal Transduction; Sports; TBI Patients; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Transportation; Traumatic Brain Injury; Vehicle crash; Vesicle; Western Blotting; Work; aged; base; comorbidity; controlled cortical impact; disability; experimental study; extracellular; extracellular vesicles; falls; improved; in vivo; inflammatory milieu; injured; innovation; insight; macrophage; neutralizing antibody; neutrophil; prevent; recruit; systemic inflammatory response; therapeutic target; tissue injury; uptake

PROJECT SUMMARY The overall goal of this project is to determine whether TBI-induced inflammatory changes result in peripheral organ damage that is dependent on activation of the inflammasome by extracellular vesicles (EV) and ASC specks. Our recent work has shown that a crucial part of the TBI-induced systemic inflammatory response involves release of extracellular vesicles containing a cargo of innate immune proteins that are secreted from damaged central nervous system (CNS) tissue. Importantly, EV and ASC specks from TBI animals induce inflammasome activation in peripheral organs. The specific aims of this proposal will determine the cellular and molecular mechanisms regulating EV- and ASC speck-mediated innate immune inflammatory reactions in peripheral organs after TBI. The hypothesis of this study is that EV and ASC specks play a central role in innate immune signaling by carrying inflammasome proteins to peripheral organs after TBI, thus causing tissue injury. Moreover, neutralization of secreted ASC with a monoclonal antibody decreases peripheral organ damage after TBI, resulting in improved histopathological outcomes. Aim 1 will determine if TBI alters the composition of EV proteins in brain, peripheral organs and bodily fluids. These studies will delineate a protein profile of EV proteins after TBI. Aim 2 will establish if ASC specks accumulate in brain and peripheral organs after TBI and induce an inflammatory responses leading to pyroptosis. We will investigate whether the activation of inflammasomes in vivo leads to the appearance of ASC specks and whether the deposition of ASC specks in tissues induces the recruitment of neutrophils and lymphocytes, thus contributing to the inflammatory milieu in peripheral organs. Aim 3 will determine the therapeutic effects of antibody neutralization of the inflammasome on histopathological outcomes after TBI. These studies will provide critical information about the activation patterns of innate immunity regulated by EV and ASC specks in the CNS, and identify relevant therapeutic targets to control inflammation following TBI and other neurodegenerative disorders.

项目摘要 该项目的总体目标是确定TBI引起的炎症变化是否导致周围 依赖细胞外囊泡（EV）和ASC激活炎症体的器官损伤 斑点。我们最近的工作表明，TBI引起的全身炎症反应的关键部分 涉及释放包含来自先天免疫蛋白的货物的细胞外囊泡 中枢神经系统（CNS）组织受损。重要的是，来自TBI动物的EV和ASC诱导 外围器官中的炎性体激活。该提案的具体目的将决定细胞和 调节EV和ASC介导的先天免疫反应的分子机制 TBI之后的外围器官。这项研究的假设是EV和ASC斑点在 先天免疫信号传导通过将炎性蛋白携带到TBI后的外围器官，从而导致组织 受伤。此外，用单克隆抗体的分泌ASC中和降低外周器官 TBI后的损害，导致组织病理学结果改善。 AIM 1将确定TBI是否改变 大脑，外围器官和体液中EV蛋白的组成。这些研究将描述蛋白质 TBI后EV蛋白的概况。 AIM 2将确定ASC斑点是否在大脑和外围器官中积聚 在TBI并诱导炎症反应后导致凋亡。我们将调查是否 体内炎症体的激活导致ASC斑点的出现，以及是否沉积 组织中的ASC斑点诱导中性粒细胞和淋巴细胞的募集，从而有助于 外围器官中的炎症环境。 AIM 3将确定抗体中和的治疗作用 TBI之后的组织病理学结果的炎性体。这些研究将提供关键信息 关于CNS中EV和ASC斑点调节的先天免疫的激活模式，并识别 TBI和其他神经退行性疾病后控制炎症的相关治疗靶标。