LITAF regulation of cell death and inflammatory responses

LITAF 调节细胞死亡和炎症反应

基本信息

批准号：
10886166
负责人：
Adam Lacy-Hulbert
金额：
$ 29.96万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10886166
关键词：
Affect Applications Grants Bacterial Infections Biochemical Cell Death Cell Death Induction Cell Survival Cell membrane Cell model Cells Cellular Stress Cellular biology Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Data Defense Mechanisms Disease Epithelial Cells Epithelium Equilibrium Genes Genetic Screening Hemolysin High-Throughput DNA Sequencing Homeostasis Host Defense Immune Immune signaling Immunity In Vitro Infection Inflammasome Inflammation Inflammatory Inflammatory Response Knock-out Knockout Mice Link Lung Lung infections Macrophage Mechanics Mediating Membrane Membrane Proteins Mission Molecular Biology Mus Mutagenesis Mutation Nutrient Pathologic Pathology Pathway interactions Play Pneumonia Production Pulmonary Inflammation RNA Interference Regulation Reporting Research Resistance Role Signal Transduction Staphylococcus aureus Staphylococcus aureus infection Stress System Testing Toxin United States National Institutes of Health VDAC1 gene Vesicle airway epithelium alpha Toxin cell injury cytokine exosome experimental study human model in vivo in vivo Model inhibitor lung injury monocyte mouse model overexpression pathogen pathogenic bacteria prevent repaired response screening ubiquitin ligase

项目摘要

Project Summary Membrane damage by mechanical or biochemical stress, leads to cell death and activation of innate immune inflammatory pathways, and contributes to the pathology of many inflammatory conditions. Furthermore, pathogens can secrete pore-forming toxins (PFT) to promote infection and disrupt immunity, and endogenous pore-forming proteins such as Gasdermin D and MLKL have been shown to contribute to inflammatory signaling and secretion of cytokines. Cells have evolved multiple mechanisms to repair membrane damage and maintain cellular homeostasis, but our understanding of how damage is sensed and linked to repair remains incomplete. We have recently developed a transposon-based forward genetic screening approach, which we have used to identify genes that promote resistance to cell death induced by S. aureus α-toxin. We identified the lysosomal membrane protein LITAF as a cell-autonomous inhibitor of cell death. In preliminary data, we show that LITAF promotes sequestration of damaged membranes into vesicles through the activation of the ESCRT machinery. We hypothesize that LITAF acts as an effector of cellular defense against pore-forming proteins, linking sensing of membrane damage to effector mechanisms of repair. In this application, we propose to test this hypothesis by: (1) identifying the mechanisms of LITAF activation and function; (2) determining the role of this pathway in lung inflammation and infection; (3) testing whether LITAF regulates innate immune signaling, inflammasome activation and inflammatory cell death in macrophages. This research is of high significance as it will provide a deeper understanding of cellular defense mechanisms against membrane damage, and of the balance between cell survival and inflammatory cell death. Identifying strategies to counteract membrane damage and prevent cell death will contribute to understanding and treating the pathology of a wide range of infectious and inflammatory diseases.

项目摘要机械或生化应力损害膜损伤，导致细胞死亡和先天免疫的激活炎症途径，并导致许多炎症状况的病理。此外，病原体可以秘密形成孔形成毒素（PFT），以促进感染和破坏免疫力，并内源性孔形成蛋白（例如加油D和MLKL）已显示有助于炎症信号传导和细胞因子的分泌。细胞已经发展了多种机制来修复膜损伤并维持细胞体内稳态，但是我们对损害的感觉和与修复有关的理解仍然不完整。我们最近开发了一种基于转座子的前向基因筛查方法，我们曾经用过这种方法确定促进金黄色葡萄球菌α-毒素诱导的细胞死亡的基因。我们确定了溶酶体膜蛋白LITAF是细胞自治的细胞死亡抑制剂。在初步数据中，我们证明了Litaf 通过激活ESCRT机械，将受损机制固定为蔬菜。我们假设LITAF是针对形成孔的蛋白的细胞防御的效果，连接传感器修复效应机制的膜损害。在此应用程序中，我们建议检验此假设作者：（1）识别LITAF激活和功能的机制；（2）确定该途径在肺部炎症和感染；（3）测试LITAF是否调节先天免疫信号，炎症巨噬细胞中的激活和炎症细胞死亡。这项研究具有很高的意义，因为它将提供对膜损伤的细胞防御机制的更深入了解，以及对细胞存活和炎症细胞死亡。确定抵消膜破坏并防止的策略细胞死亡将有助于理解和治疗广泛的感染性和炎症性疾病。