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

• 批准号: 10582579
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582579
• 关键词: Address; Adult; Affect; Airway Disease; Airway Fibrosis; 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; Clinical; Clinical Data; Coupled; Data; Development; Diagnosis; Disease; Elements; Emotional; FDA approved; Fibrosis; Financial cost; Frequencies; Functional disorder; Gene Expression Profile; Genetic; Genetic Transcription; Genomics; Genus Mycobacterium; Geography; Goals; Human; IL17 gene; Immune; Immune response; Immunity; Immunologic Techniques; Individual; Infection; Infiltration; Inflammatory; International; Investigation; Jurkat Cells; Legal patent; Life; Longitudinal Studies; 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; Recurrent disease; Reporter; Research; Respiratory Mucosa; Sorting; Specificity; Stenosis; Strategic Planning; Structure; Sulfamethoxazole; T cell infiltration; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Techniques; Testing; Therapeutic; Tissue Sample; Tissues; Trachea; Trimethoprim; Woman; Work; airway obstruction; antagonist; 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

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/摘要 特发性声门下狭窄（iSGS）是一种原因不明的粘膜纤维炎性疾病， 几乎只发生在成年白人女性的上呼吸道。患者需要紧急 手术以防止因呼吸道阻塞而死亡。新的治疗方法旨在阻止 进行性气道纤维化对于减轻这种疾病的负担至关重要。鉴于其稀有性， 受影响患者的地理分布以前限制了确定基本 疾病的生物学。我们最近的出版物揭示了iSGS气道瘢痕中的微生物生态失调， 沿着炎症通路激活。利用1000例患者的国际iSGS队列 由该提案的PI（iSGS 1000）领导，该项目旨在了解 iSGS通过回答问题：iSGS与活动性感染有关，还是细菌 引发自身免疫反应我们的建议利用独立但相互关联的 解决这一问题的方法。在目标1中，我们将应用尖端的分子免疫学 和生物信息学技术分选气道瘢痕中浸润的CD 8 + T细胞， 通过RNAseq检测单个T细胞受体（TCR），然后将高频TCR克隆到体外 用于绘制抗原特异性的模型系统。这将使我们能够研究CD 8 + iSGS气道疤痕粘膜中的T细胞表现出针对细菌的克隆反应 抗原的然后在目标2中，我们将利用iSGS中细菌的全基因组测序（WGS） 气道瘢痕，以确认与iSGS的独特细菌关联。精确分子 用元转录组学分析表征细菌将提供以下新信息： 影响致病性的遗传特征。在目标3中，我们将研究目前的治疗方法如何 iSGS影响局部微生物组以及宿主免疫力。我们独立的 但相互关联的方法将有助于确定宿主和病原体如何碰撞产生致病性 iSGS中的组织纤维化。

项目成果

Modeling Recurrence in Idiopathic Subglottic Stenosis With Mobile Peak Expiratory Flow.

• DOI: 10.1002/lary.29760
• 发表时间: 2021-12
• 期刊: The Laryngoscope
• 作者: Kimura K;Du L;Berry LD;Huang LC;Chen SC;Francis DO;Gelbard A;North American Airway Collaborative (NoAAC)
• 通讯作者: North American Airway Collaborative (NoAAC)

Localizing Hormone Receptor Expression to Cellular Compartments in Idiopathic Subglottic Stenosis.

将激素受体表达定位于特发性声门下狭窄的细胞区室。

• DOI: 10.1002/lary.30856
• 发表时间: 2023
• 期刊: The Laryngoscope
• 作者: Talatala,EdwardRyanR;Clark,Evan;Ye,Wenda;Davis,RuthJ;Hillel,AlexanderT;Collins,SamuelL;Ramirez-Solano,Marisol;Sheng,Quanhu;Gelbard,Alexander
• 通讯作者: Gelbard,Alexander

Association Between Red Blood Cell Distribution Width and Outcomes of Open Airway Reconstruction Surgery in Adults.

红细胞分布宽度与成人开放气道重建手术结果之间的关联。

• DOI: 10.1001/jamaoto.2018.3793
• 发表时间: 2019
• 期刊: JAMA otolaryngology-- head & neck surgery
• 作者: Xie,DeborahX;Rehman,SaadC;Francis,DavidO;Netterville,JamesL;Garrett,CGaelyn;Gelbard,Alexander;Lipscomb,Brittany;Wootten,ChristopherT
• 通讯作者: Wootten,ChristopherT

The impact of social determinants of health on laryngotracheal stenosis development and outcomes.

• DOI: 10.1002/lary.28208
• 发表时间: 2020-04
• 期刊: The Laryngoscope
• 作者: Dang S;Shinn JR;Campbell BR;Garrett G;Wootten C;Gelbard A
• 通讯作者: Gelbard A

Impact of Procedural Variation in Endoscopic Dilation for Idiopathic Subglottic Stenosis.

内镜扩张手术变化对特发性声门下狭窄的影响。

• DOI: 10.1002/lary.31393
• 发表时间: 2024
• 期刊: The Laryngoscope
• 作者: Santapuram,Pooja;Tierney,WilliamS;Huang,Li-Ching;Chen,Sheau-Chiann;Berry,LynnD;Francis,DavidO;Gelbard,Alexander
• 通讯作者: Gelbard,Alexander