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Molecular Interrogation of the Host-Pathogen Interface in Idiopathic Subglottic Stensosis

特发性声门下狭窄宿主-病原体界面的分子研究

基本信息

批准号：
9900067
负责人：
Alexander Gelbard
金额：
$ 38.25万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900067
关键词：
Address Adult Affect Airway Disease Antibiotics Antigens Automobile Driving Bacteria Bacterial Antigens Bacterial Infections Bioinformatics Biological Models Biology Biopsy CD8-Positive T-Lymphocytes CD8B1 gene Caucasians Cell Line Cells Cessation of life Cicatrix Clinical Clinical Data Coupled Data Development Disease Elements Emotional FDA approved Fibrosis Financial cost Frequencies Functional disorder Gene Expression Profile Genetic Genetic Transcription Genomics Genus Mycobacterium Geography Goals Human Immune Immune response Immunity Immunologic Techniques Individual Infection Inflammatory Interleukin-17 International Investigation Jurkat Cells Life Luciferases Maps Memory Microscopic Molecular Molecular Immunology Mucositis Mucous Membrane National Heart, Lung, and Blood Institute Operative Surgical Procedures Outcome Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Positioning Attribute Precision therapeutics Proteins Publications Publishing Recording of previous events Recurrence Research Specificity Stenosis Structure Sulfamethoxazole T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Techniques Testing Therapeutic Tissue Sample Tissues Trimethoprim-Sulfamethoxazole Tumor-infiltrating immune cells Woman Work airway obstruction bacterial community biobank burden of illness cohort design dysbiosis genome sequencing immune activation improved in vitro Model innovation metagenomic sequencing metatranscriptomics microbial microbiome microbiome composition molecular phenotype mycobacterial novel novel therapeutics pathogen pathogen exposure peripheral blood prevent response transcriptome transcriptome sequencing whole genome

项目摘要

Project Summary/Abstract Idiopathic subglottic stenosis (iSGS) is an unexplained mucosal fibroinflammatory disease of the upper airway that occurs almost exclusively in adult, Caucasian women. Patients require urgent surgery to prevent death from airway obstruction. Novel therapies aimed at halting the progressive airway fibrosis are critical to reduce the burden of this disease. Given its rarity, the geographical dispersal of affected patients has previously limited investigations to define the basic biology of the disease. Our recent publications reveal microbial dysbiosis in iSGS airway scar, along with inflammatory pathway activation. Leveraging a 1000-patient international iSGS cohort led by this proposal’s PI (iSGS1000), this project is designed to understand the pathogenesis of iSGS by answering the question: Is iSGS related to an active infection, or does bacteria trigger a self-reactive immune response. Our proposal utilizes independent but interrelated approaches to address this question. In Aim 1 we will apply cutting edge molecular immunology and bioinformatic techniques to sort infiltrating CD8+ T cells from airway scar, directly sequence individual T cell receptors (TCR) via RNAseq, then clone high frequency TCRs into an in vitro model system to map antigen specificity. This will allow us to investigate the hypothesis that CD8+ T cells in the mucosa of iSGS airway scar demonstrate a clonal response directed at a bacterial antigen. Then in Aim 2 we will utilize whole genome sequencing (WGS) of the bacteria in iSGS airway scar to confirm a unique bacterial association with iSGS. Precise molecular characterization of the bacteria with metatranscriptomic analysis will provide new information on genetic features impacting pathogenicity. In Aim 3 we will investigate how current treatments for iSGS impact both the local microbiome as well as host immunity. Taken together our independent but interrelated approaches will help define how host and pathogen collide to produce pathogenic tissue fibrosis in iSGS.

项目总结/文摘