Cytosolic Immune Surveillance During Bacterial Infections

炎症体感知一系列病原体相关分子模式(PAMP)和 在感染和创伤期间产生的损害相关分子模式(DAMP)和 代表着对抗感染的第一道防线。在规范形式中，炎性小体由 识别PAMPs的传感器蛋白、适配器分子ASC和效应器蛋白酶， Caspase-1。在非规范形式中，炎性caspase与caspase-1有关，即 Caspase-11和caspase-4，直接从Gram-2中感受胞内脂多糖(LPS)。 阴性菌及其外膜囊泡。炎症体信号在 IL-1β、IL-18、Gasdermin D(一种成孔蛋白)和下垂的翻译后激活， 细胞死亡的一种溶解和发炎的形式，同时释放湿气。尽管 炎症体反应在感染、癌症和自身免疫中的深远意义 微调炎症小体信号的启动和终止的调节模块仍然存在 大部分都是未知的。这项建议寻求全面解决这一关键的知识差距 关注Galectins的三个特定目标，Galectins是一种β-半乳糖苷结合蛋白家族。由于 它们与各种糖蛋白的N-或O-糖链末端结合并调节它们的 膜定位和信号转导，Galectins在不同的细胞中具有不同的功能 生理和病理过程。该提案的目标1和2将调查Galectins的 在小鼠、人类细胞和体内非典型炎症体信号传递中的作用。目标3将 探索Galectins如何在体外和体内控制典型的炎症体信号。总而言之， 该项目的发现将揭示炎症体信号中的新角色，具有重要意义 对人类传染病和败血症的影响。

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.