Host-derived extracellular vesicles in inflammatory caspase activation

宿主来源的细胞外囊泡在炎症半胱天冬酶激活中的作用

基本信息

批准号：
10535447
负责人：
Vijay Rathinam
金额：
$ 41万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-16 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535447
关键词：
Address Albumins Antibiotics Bacteria Bacterial Infections Binding Biochemical Blood CASP1 gene CD14 gene CD47 gene CRISPR screen Caspase Cell Death Cell Fractionation Cell Wall Cell membrane Cell surface Cells Chronic Circulation Communicable Diseases Complement Complex Confocal Microscopy Coupled Cre-LoxP Cytolysis Cytosol Detection Development Disease Distant Electrons Endosomes Endothelial Cells Event Extracellular Space Family Flagellin Flow Cytometry Genetic Transcription HMGB1 gene Host Defense Human IL18 gene Image Immune Immune response Immunologic Surveillance In Situ In Vitro Infection Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune System Integration Host Factors Interleukin-1 Interleukin-1 beta Knowledge Leaky Gut Life Lipids Literature Location Lytic Mass Spectrum Analysis Mediating Membrane Methods Microscopic Molecular Multiprotein Complexes Mus Mutant Strains Mice Myeloid Cells Nucleic Acids Outcome Pathway interactions Pattern Pattern recognition receptor Perforation Pharmaceutical Preparations Physiology Play Proteins RNA Regulation Role Sepsis Signal Transduction Structure TLR4 gene Toxin Translational Activation Uric Acid VDAC1 gene Vesicle Virus Work cell type cytokine defined contribution extracellular vesicles immunoregulation in vivo insight lipopolysaccharide-binding protein microbial products pathogen response virtual

项目摘要

Inflammasome related caspases such as caspase-1, caspase-4, and caspase-11 are a subset of the caspase family specialized in executing a lytic form of cell death and IL-1 cytokine-based inflammatory response. The activation of these inflammatory caspases is strongly coupled to innate immune detection of infections and cellular perturbations via canonical and noncanonical inflammasomes. Inflammasomes are multiprotein complexes in the cytosol assembled in response to wide variety of pathogen-associated molecular patterns (PAMPs) including nucleic acids, toxins, flagellin, and cell wall components and endogenous danger signals (danger- associated molecular patterns, or DAMPs) such as ATP and uric acid crystals. The assembly of inflammasome complex leads to the autoproteolytic activation of inflammatory caspases. Enzymatically active versions of inflammatory caspases activate a pore forming protein called gasdermin D, which lyses the cells via plasma membrane perforation. Active caspase-1 also cleaves the inflammatory cytokines pro-IL-1β and pro-IL-18 into their active forms. Inflammatory caspases are important for initiating the inflammatory response against a wide variety of pathogens including bacteria and viruses. Inflammatory caspases also play crucial roles in sepsis, a major life-threatening condition associated with infections. Extracellular vesicles (EVs) are membrane-bound structures abundantly released by our living cells into the extracellular space. EVs are packaged with proteins, lipids, and RNAs, and EVs have emerged as a crucial mode of inter-cellular transfer of all three cargoes. EV-cargoes are functional and modulate the physiology of the recipient cells. However, the role of EVs in the inflammasome signaling is poorly understood. This proposal seeks to comprehensively address this critical knowledge gap in three specific aims. Aim 1 will characterize the impact of host-derived EVs on inflammatory caspase activation by PAMPs. Aims 2 and 3 will demonstrate the molecular and cellular mechanisms by which the host-derived EVs regulate PAMP-activation of inflammatory caspases. In summary, this proposal will reveal a new role for host-derived EVs in inflammasome responses in the context of host defense with great implications for human infectious diseases and sepsis.

与炎性体相关的caspase，例如caspase-1，caspase-4和caspase-11是一个子集 caspase家族专门执行细胞死亡和IL-1基于IL-1细胞因子的裂解形式炎症反应。这些炎症胱天蛋白酶的激活与通过规范和非规范的感染和细胞扰动的先天免疫检测和细胞扰动炎症。炎性症是组装的细胞质中的多蛋白复合物对各种病原体相关的分子模式（PAMP）的反应，包括核。酸，毒素，鞭毛和细胞壁成分以及内源性危险信号（危险 - 相关的分子图案，或潮湿），例如ATP和尿酸晶体。组装炎症体复合物导致炎症性胱天蛋白酶的自传溶解活化。促炎性胱天蛋白酶的酶活性版本激活一种形成的孔形成蛋白 Gasdermin D，通过质膜穿孔裂解细胞。活性caspase-1 将炎性细胞因子pro-IL-1β和pro-IL-18切割成其活性形式。胱天蛋白酶对于发起炎症反应很重要病原体包括细菌和病毒。炎症性胱天蛋白酶在败血症中也起着至关重要的作用，与感染有关的主要威胁生命的疾病。细胞外蔬菜（EV）是膜结合的结构绝对由我们的活细胞释放到细胞外空间中。电动汽车用蛋白质，脂质和RNA包装，EV已成为一种关键模式所有三个货物的细胞间转移。 EV-Cargoes具有功能性并调节生理接受者细胞。但是，电动汽车在炎性体信号传导中的作用很差理解。该建议旨在全面解决这一关键知识差距具体目标。 AIM 1将表征宿主衍生的电动汽车对炎症caspase的影响通过弹药的激活。目标2和3将通过宿主衍生的电动汽车调节炎症性胱天蛋白酶的PAMP激活。总而言之，这提案将在炎症中的炎症反应中揭示宿主衍生的电动汽车的新作用主持人防御对人类传染病和败血症具有很大的影响。