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: 10228550
• 负责人: Eugene H Chang
• 金额: $ 56.69万
• 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/10228550
• 关键词: Address; Adult; Affect; Age; Air; Alleles; Antiviral Agents; Binding; Biological Response Modifier Therapy; C cadherin; Cadherins; Child; Childhood; Chronic Sinusitis; Complex; Congestive; Cytokine Signaling; Data; Detection; Development; Direct Costs; Disease; Disease Progression; Drainage procedure; Epithelial; 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; Lead; Liquid substance; Mesenchymal; Molecular; Morbidity - disease rate; Mucous Membrane; Multicenter Studies; Nose; Operative Surgical Procedures; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Persons; Population; 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; base; 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）感染在整个年龄，性别和种族之间无处不在，是最常见的原因 用于医疗访问。在大多数受影响的人中，RV感染的症状是轻度和自限制的。 然而，在患有慢性鼻炎（CRS）的人中，RV感染是CRS恶化的主要原因 和相关的发病率。最近，我们发现RV-C物种在成年人中很常见，并且RV-C感染 与研究良好的RV-A和RV-B物种相比，会导致更大的鼻窦症状。我们也是 确定RS6967330是最近发现的RV-C Cadherin相关系列中的遗传风险变体 成员3（CDHR3）病毒受体，导致成人CR的几率增加了两倍。虽然CRS是一个 异质性疾病，手术组织的转录组研究已确定明显的失调 与趋化因子/细胞因子信号传导和上皮间质转变（EMT）相关的基因。这 此应用的目的是（i）确定CRS和RS6967330 CDHR3风险等位基因的受试者是否存在 与患有RV-C感染相比，具有不同的分子内型 更频繁的野生型等位基因和（ii）确定具有RS6967330等位基因的成人CRS受试者是否更多 与RV-A和RV-B感染相比，与RV-C感染相比，CRS可能会加重RV-C感染。我们 假设在体外研究具有RS6967330 CDHR3风险等位基因的空气 - 液体界面（ALI）培养物将 产生一个以（i）增加RV-C结合和复制为特征的分子内型，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）差异表达的基因（DEGS） 与表达野生型等位基因的上皮相比，与气道重塑相关的EMT途径。 同样，我们假设我们对具有RS6967330等位基因的CRS受试者的体内研究将揭示 CRS的数量增加了继发于RV-C感染的特征是增加 感染后气道重塑的鼻腔症状，鼻细胞因子的产生和转录组变化。 迫切需要了解分子机制，这些机制是提高的致病性的基础 RV-C感染rs6967330 CDHR3的人有风险等位基因，以告知新目标的发展 预防和减慢CR的进展的策略。