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The role of Gasdermin E (DFNA5) in bacterial keratitis

Gasdermin E (DFNA5) 在细菌性角膜炎中的作用

基本信息

批准号：
10393056
负责人：
GEORGE R DUBYAK
金额：
$ 19.28万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393056
关键词：
Adoptive Transfer Autophagocytosis Autophagosome Azurophilic Granule Bacteria Bacterial Infections Biochemical Budgets C57BL/6 Mouse CASP1 gene CASP3 gene Caspase Cell Death Cell Line Cell Membrane Permeability Cell membrane Cells Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Communication Cornea Corneal Diseases Corneal Opacity Corneal Stroma Cytoplasmic Granules Cytosol Data Family Family member Funding Genetic Transcription Growth Histones Human Immune Immune Targeting Immune response In Vitro Infection Inflammasome Inflammation Inflammatory Interleukin-1 beta Keratitis Knock-out Leukocyte Elastase Malignant Neoplasms Matrix Metalloproteinases Mediating Mediator of activation protein Membrane Modeling Molecular Mus Nature Neutrophil Activation Organelles Paper Pathogenesis Pathway interactions Peptide Hydrolases Play Principal Investigator Production Protease Inhibitor Protein Family Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection Regulation Reporting Resolution Role Serine Serine Protease Serpins Severities Signal Transduction Source Stimulus Streptococcus pneumoniae Tissues VDAC1 gene base corneal scar cytokine extracellular immunological intervention insight member microbial microbicide neutrophil novel pathogen pathogenic bacteria preservation prevent response trafficking transcriptome sequencing

项目摘要

PROJECT ABSTRACT Gasdermin (GSDM) A-E comprise a family of pore-forming proteins that are associated with infection, inflammation and cancer. RNAseq analysis revealed that the only GSDM family members expressed by neutrophils are Gsdmd and Gsdme/DFNA5, and preliminary data show that neutrophils can activate caspase- 3, which cleaves pro- GSDME to the pore-forming N-GSDME to drive formation of plasma membrane pores leading to pro-inflammatory pyroptotic cell death. This is in contrast to results from our Nature Communications 2020 paper showing that that GSDMD activated by caspase-1 and neutrophil elastase in neutrophils occurs in the absence of pyroptotic cell death. Both GSDMD and GSDME mediate neutrophil production of bioactive IL- 1β, which we reported is a pivotal cytokine in the host immune response that is required to regulate Streptococcus pneumoniae and Pseudomonas aeruginosa bacterial growth and corneal opacification. We propose to characterize GSDME regulation and function in neutrophils in response to S. pneumoniae and P. aeruginosa in vitro, and to define the vivo role(s) of GSDME in keratitis caused by these pathogenic bacteria. Aim 1 will characterize GSDME regulation and function in neutrophils and define its role in coordinating neutrophil pyroptotic cell death and formation of neutrophil extracellular traps in response to S. pneumoniae or P. aeruginosa. Aim 2 will characterize GSDME processing in infected corneas, and assess the role of GSDME in S. pneumoniae or P. aeruginosa using GSDME-/- and GSDME-/-/GSDMD-/- mice in neutrophil viability, bacterial killing and the severity of corneal disease, and will use an adoptive transfer model to examine the role of neutrophil GSDME. Results of the proposed studies will provide insight into the role of these pore forming proteins in neutrophil responses to these ocular pathogens, and will identify potential targets for immune intervention in bacterial keratitis.

项目摘要