Interactions between RV-C and its receptor CDHR3 in the development of chronic rhinosinusitis

RV-C与其受体CDHR3在慢性鼻-鼻窦炎发生过程中的相互作用

• 批准号: 10671731
• 负责人: Eugene H Chang
• 金额: $ 54.67万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-04 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671731
• 关键词: Address; Adult; Affect; Age; Air; Alleles; Binding; Biological Response Modifier Therapy; C cadherin; Cadherins; Child; Childhood; Chronic Sinusitis; Complex; Cytokine Signaling; Data; Detection; Development; Direct Costs; Disease; Disease Progression; Drainage procedure; Epithelium; Ethnic Origin; Facial Pain; Facilities and Administrative Costs; Family member; Foundations; Functional disorder; Gender; Genes; Genetic Risk; Goals; Health Care Costs; Health Care Visit; Human; Immunity; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory Response; Inflammatory Response Pathway; Knowledge; Liquid substance; Mesenchymal; Molecular; Morbidity - disease rate; Mucous Membrane; Multicenter Studies; Nose; Operative Surgical Procedures; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Persons; Population; Predisposition; Production; Public Health; Reporting; Research; Rhinovirus; Rhinovirus infection; Risk; Role; Secondary to; Serotyping; Severities; Severity of illness; Signal Transduction; Sinusitis; Surface; Symptoms; Testing; Tissues; Upper Respiratory Infections; Viral; Virus; Virus Diseases; Virus Receptors; airway remodeling; chemokine; chronic rhinosinusitis; cytokine; differential expression; epidemiology study; genetic risk factor; in vivo; infection risk; novel strategies; prevent; receptor; response; risk variant; transcriptome; transcriptomics

PROJECT ABSTRACT Rhinovirus (RV) infections are ubiquitous across age, gender, and ethnicity and are the most frequent reason for healthcare visits. In the majority of affected persons, the symptoms of RV infections are mild and self-limiting. In persons with chronic rhinosinusitis (CRS), however, RV infections are a major cause of CRS exacerbations and associated morbidity. Recently, we found that RV-C species are common in adults, and that RV-C infections result in greater sinonasal symptoms compared with the well-studied RV-A and RV-B species. We also determined that rs6967330, a genetic risk variant in the recently discovered RV-C Cadherin Related Family Member 3 (CDHR3) viral receptor, causes a two-fold increase in the odds for adult CRS. Although CRS is a heterogeneous disorder, transcriptome studies of surgical tissues have determined significant dysregulation of genes associated with chemokine/cytokine signaling and epithelial-mesenchymal transitions (EMT). The objective of this application is to (i) determine if subjects with CRS and the rs6967330 CDHR3 risk allele have a different molecular endotype in response to RV-C infections as compared with those with the more frequent wild-type allele and (ii) determine if adult CRS subjects with the rs6967330 allele are more likely to have CRS exacerbations with RV-C infections compared to RV-A and RV-B infections. We hypothesize that in vitro studies of air-liquid-interface (ALI) cultures with the rs6967330 CDHR3 risk allele will generate a molecular endotype characterized by (i) increased RV-C binding and replication, ii) increased cytokines/chemokines associated with types 1 and 2 immunity, and iii) differentially expressed genes (DEGs) and EMT pathways associated with airway remodeling compared to epithelia expressing the wild-type allele. Likewise, we hypothesize that our in vivo studies of CRS subjects with the rs6967330 allele will reveal an increased number of CRS exacerbations secondary to RV-C infections that are characterized by increased sinonasal symptoms, nasal cytokine production, and transcriptomic changes in airway remodeling after infection. There is a critical need to understand the molecular mechanisms that underlie the increased pathogenicity of RV-C infections in persons with the rs6967330 CDHR3 risk allele to inform the development of new targeted strategies to prevent and slow the progression of CRS.

项目摘要 鼻病毒 (RV) 感染在不同年龄、性别和种族中普遍存在，并且是最常见的原因 用于医疗保健就诊。对于大多数受影响的人来说，RV 感染的症状很轻微并且具有自限性。 然而，在慢性鼻窦炎 (CRS) 患者中，RV 感染是 CRS 恶化的主要原因 以及相关的发病率。最近，我们发现 RV-C 物种在成人中很常见，并且 RV-C 感染 与经过充分研究的 RV-A 和 RV-B 物种相比，这种病毒会导致更严重的鼻窦症状。我们也 确定了 rs6967330，这是最近发现的 RV-C 钙粘蛋白相关家族中的遗传风险变异体 成员 3 (CDHR3) 病毒受体，导致成人 CRS 的几率增加两倍。虽然 CRS 是一个 异质性疾病，手术组织的转录组研究已经确定了显着的失调 与趋化因子/细胞因子信号传导和上皮间质转化（EMT）相关的基因。这 本申请的目的是 (i) 确定受试者是否患有 CRS 和 rs6967330 CDHR3 风险等位基因 与 RV-C 感染相比，具有不同的分子内型 更常见的野生型等位基因，以及 (ii) 确定具有 rs6967330 等位基因的成年 CRS 受试者是否更常见 与 RV-A 和 RV-B 感染相比，RV-C 感染可能导致 CRS 恶化。我们 假设对具有 rs6967330 CDHR3 风险等位基因的气液界面 (ALI) 培养物进行体外研究将 产生一种分子内型，其特征在于 (i) RV-C 结合和复制增加，ii) 增加 与 1 型和 2 型免疫相关的细胞因子/趋化因子，以及 iii) 差异表达基因 (DEG) 与表达野生型等位基因的上皮细胞相比，EMT 途径与气道重塑相关。 同样，我们假设我们对带有 rs6967330 等位基因的 CRS 受试者的体内研究将揭示 继发于 RV-C 感染的 CRS 恶化数量增加，其特征是增加 鼻窦症状、鼻细胞因子的产生以及感染后气道重塑的转录组变化。 迫切需要了解致病性增加的分子机制 带有 rs6967330 CDHR3 风险等位基因的人的 RV-C 感染，为新靶向药物的开发提供信息 预防和减缓 CRS 进展的策略。

项目成果

Viral infections and chronic rhinosinusitis.

病毒感染和慢性鼻窦炎。

• DOI: 10.1016/j.jaci.2023.07.018
• 发表时间: 2023-08-01
• 期刊: The Journal of allergy and clinical immunology
• 作者: Sophia Volpe;J. Irish;Sunny Palumbo;Eric Y. Lee;Jacob Herbert;I. Ramadan;Eugene H. Chang
• 通讯作者: Eugene H. Chang

The GSDMB rs7216389 SNP is associated with chronic rhinosinusitis in a multi-institutional cohort.

在多机构队列中，GSDMB rs7216389 SNP 与慢性鼻鼻窦炎相关。

• 发表时间: 2021-12
• 作者: Zack, Dana E;Stern, Debra A;Willis, Amanda L;Kim, Alexander S;Mansfield, Corinne J;Reed, Danielle R;Brooks, Steven G;Adappa, Nithin D;Palmer, James N;Cohen, Noam A;Chiu, Alexander G;Song, Brian H;Le, Chris H;Chang, Eugene H
• 通讯作者: Chang, Eugene H

Development of a self-directed sinonasal surgical anatomy video curriculum: Phase 1 validation.

自主鼻腔鼻腔外科解剖视频课程的开发：第一阶段验证。

• 发表时间: 2021
• 作者: Bailey, C Eric;Grauer, Jordan S;Chen, Philip G;Rangarajan, Sanjeet V;Chan, Yvonne;Tewfik, Marc A;Marino, Michael J;Torabi, Mohammad;Le, Christopher H;Chang, Eugene H
• 通讯作者: Chang, Eugene H

Genetics of chronic rhinosinusitis.

慢性鼻窦炎的遗传学。

• DOI: 10.1016/j.jaci.2020.01.029
• 发表时间: 2020-01-30
• 期刊: The Journal of allergy and clinical immunology
• 作者: Kyle Mitts;Eugene H Chang
• 通讯作者: Eugene H Chang

How our specialty can contribute and benefit from COVID-19 research.

我们的专业如何为 COVID-19 研究做出贡献并从中受益。

• 发表时间: 2020
• 作者: Chang; Eugene H
• 通讯作者: Eugene H