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Cytosolic Immune Surveillance During Bacterial Infections

细菌感染期间的细胞质免疫监视

基本信息

批准号：
10306046
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：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10306046
关键词：
Address Anti-Bacterial Agents Autoimmunity Bacteria Bacterial Infections Binding Binding Proteins Biological Assay Burkholderia Infections CASP1 gene Carbohydrates Caspase Cell Death Cells Communicable Diseases Confocal Microscopy Coupled Cytosol DNA Disease Endosomes Event Excision Family Francisella Galactose Binding Lectin Galactosides Galectin 3 Glycoproteins Gram-Negative Bacteria Homeostasis Host Defense Human Image Immune Immunologic Surveillance Impairment In Vitro Infection Inflammasome Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-18 Knockout Mice Knowledge Label Licensing Life Link Lipopolysaccharides Lytic Macromolecular Complexes Malignant Neoplasms Mass Spectrum Analysis Mediating Membrane Modeling Molecular Monitor Mus Pathologic Processes Pathway interactions Pattern Peptide Hydrolases Physiological Processes Play Polysaccharides Process Proteins Regulation Resolution Role Salmonella Sepsis Series Shapes Side Signal Transduction Specificity Translational Activation Trauma VDAC1 gene Vacuole Vesicle Virus Diseases antimicrobial base carbohydrate binding protein cell type guanylate immunoregulation in vivo insight microbial mutant pathogen pathogenic Escherichia coli repaired response sensor

项目摘要

Inflammasomes sense an array of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) generated during infection and trauma and represent the first line of defense against infections. In the canonical form, inflammasomes consist of a sensor protein that recognizes PAMPs, an adaptor molecule ASC, and an effector protease, caspase-1. In the noncanonical form, inflammatory caspases related to caspase-1, namely caspase-11 and caspase-4, directly sense cytosolic lipopolysaccharide (LPS) from Gram- negative bacteria and their outer membrane vesicle. Inflammasome signaling culminates in the post-translational activation of IL-1β, IL-18, gasdermin D (a pore-forming protein), and pyroptosis, a lytic and inflammatory form of cell death, and the simultaneous release of DAMPs. Despite the profound implications of inflammasome responses in infections, cancer, and autoimmunity, the regulatory modules that fine-tune the initiation and termination of inflammasome signaling remain mostly unknown. This proposal seeks to comprehensively address this critical knowledge gap in three specific aims by focusing on galectins, a family of β-galactoside-binding proteins. Owing to their capacity to bind to N- or O-glycan termini of various glycoproteins and regulate their membrane localization and signal transduction, galectins have diverse functions in various physiological and pathological processes. Aims 1 and 2 of the proposal will investigate galectins' role in noncanonical inflammasome signaling in murine and human cells and in vivo. Aim 3 will explore how galectins control canonical inflammasome signaling in vitro and in vivo. In summary, the findings from this project would reveal new players in inflammasome signaling with significant implications for human infectious diseases and sepsis.

炎症小体感知一系列病原体相关分子模式（PAMP）并感染和创伤期间产生的损伤相关分子模式（DAMP）是抵御感染的第一道防线。在规范形式中，炎症小体由识别 PAMP 的传感器蛋白、衔接分子 ASC 和效应蛋白酶，胱天蛋白酶-1。在非规范形式中，炎症性 caspase 与 caspase-1 相关，即 caspase-11 和 caspase-4，直接检测革兰氏阴性菌的胞质脂多糖 (LPS) 阴性菌及其外膜囊泡。炎症小体信号传导达到顶峰 IL-1β、IL-18、gasdermin D（一种成孔蛋白）的翻译后激活和细胞焦亡，一种溶解性和炎症性的细胞死亡，同时释放 DAMP。尽管炎症小体反应对感染、癌症和自身免疫的深远影响微调炎症小体信号传导的启动和终止的调节模块仍然存在大多不为人知。该提案旨在全面解决这一关键知识差距通过关注半乳糖凝集素（β-半乳糖苷结合蛋白家族）来实现三个具体目标。由于它们与各种糖蛋白的 N-或 O-聚糖末端结合并调节它们的能力半乳糖凝集素在膜定位和信号转导方面具有多种功能生理和病理过程。该提案的目标 1 和 2 将研究半乳糖凝集素的作用在小鼠和人类细胞以及体内的非典型炎症体信号传导中的作用。目标3将探索半乳糖凝集素如何在体外和体内控制经典炎症小体信号传导。总之，该项目的研究结果将揭示炎症小体信号传导中的新参与者，具有显着的意义对人类传染病和败血症的影响。