The role of galectin-8 in the regulation of corneal infection and inflammation

Galectin-8在调节角膜感染和炎症中的作用

• 批准号: 9788094
• 负责人: Noorjahan Panjwani
• 金额: $ 41.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788094
• 关键词: Affect; Animals; Bacteria; Bacterial Infections; Binding; Biochemical; Blindness; CASP1 gene; Cells; Cleaved cell; Communicable Diseases; Contact Lenses; Cornea; Data; Development; Disease; Eye diseases; Galactose Binding Lectin; Gene Expression Profiling; Generations; Goals; Graft Rejection; Gram-Negative Bacteria; Immune response; Immunologics; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injections; Innate Immune Response; Innate Immune System; Interleukin-1 beta; Interleukin-18; Invaded; Keratitis; Keratoplasty; Knock-out; Knockout Mice; Leukocyte Elastase; Mediating; Microbe; Modeling; Molecular; Mus; Neutrophil Infiltration; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pattern recognition receptor; Pilot Projects; Play; Prevention strategy; Process; Proteome; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Reaction; Regulation; Resistance; Risk Factors; Role; Serine Protease; Signal Transduction; TLR2 gene; TLR4 gene; TLR5 gene; Testing; United States; Visual impairment; Wild Type Mouse; autoimmune uveitis; base; cell type; chemokine; cytokine; design; expectation; experimental study; eye dryness; immunopathology; knockout animal; macrophage; microbial; mouse model; neutrophil; neutrophil elastase inhibitor; novel; pathogen; transcriptome; transcriptome sequencing

Project Summary The bacterium Pseudomonas aeruginosa (PA) is a leading cause of microbial infection of the cornea. One of the serious consequences of PA corneal infection is blindness resulting from persistent corneal inflammation. Approximately 30,000 cases of microbial keratitis occur annually in the United States. The innate immune system is the first line of defense against pathogens and is initiated by pattern recognition receptors which respond to invading microbes. It is known that IL-1β plays an important role in the induction of immune response in PA keratitis. In the classical immune response to bacterial infection, generation of mature IL-1β is a two-step process. The first step is the induction of pro-IL-1β expression, which is generally achieved by TLR-mediated activation of NF-B pathway that results in the induction of pro-IL-1β. A second signal then triggers the assembly of inflammasomes leading to the cleavage of caspase-1. Active (cleaved) caspase-1 cleaves pro-IL-1β to generate active IL-1β, which is secreted from the cell to mediate downstream inflammatory effects that clear the infection. Recently, we have made an exciting observation that galectin-8 knockout (Gal-8 KO) mice are resistant to PA infection. Additional pilot studies revealed that Gal-8 has the potential to regulate the activation of both TLR and inflammasome pathways. The goal of this project is to characterize the role of Gal-8 in the regulation of PA-induced immunopathology, and to develop effective strategies for prevention and regression of uncontrolled inflammatory response that results in extensive damage to the cornea and visual impairment. In Aim 1, in an effort to understand the mechanisms that render Gal-8 KO mice resistant to PA keratitis, we will test the hypothesis that Gal-8 has the capacity to dampen inflammasome-mediated generation of mature IL-1β to influence innate immune response. Specifically, in this Aim, using Gal-8 KO mice and Gal-8 deficient macrophages and neutrophils, we will characterize the role of Gal-8 in the regulation of the inflammasome pathway in PA keratitis. In Aim 2, we will determine whether Gal-8 influences the outcome of PA keratitis by modulating neutrophil elastase and/or TLR pathway. To better characterize the role of Gal-8 in the pathogenesis of PA keratitis, in Aim 3A, we propose to perform transcriptome and cytokine/chemokine proteome analyses of PA-infected corneas of WT and Gal-8 KO mice, and WT and Gal-8 KO macrophages and neutrophils. In Aim 3B, studies will be performed to determine whether Gal-8 can be targeted to control overactive immune response and corneal inflammation in the mouse model of PA keratitis. We expect that the proposed study will provide ground-breaking data, not only for understanding the molecular mechanism of PA keratitis, but also for the development of novel, galectin-based therapy that can treat blinding immunopathology resulting both from bacterial keratitis, as well as from other ocular disorders, such as corneal graft rejection and dry eye disease.

项目总结