ORMDL3 Stimulated ICAM1 and RVA-induced Childhood Asthma Exacerbations

ORMDL3 刺激 ICAM1 和 RVA 诱导的儿童期哮喘加重

基本信息

批准号：
10369612
负责人：
Joshua Kennedy
金额：
$ 23.17万
依托单位：
ARKANSAS CHILDREN'S HOSPITAL RES INST
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：
2021-03-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369612
关键词：
17q21 A549 Accident and Emergency department Address Affect Agonist Allergic Architecture Asthma Automobile Driving Cadherins California Carbachol Cell Culture Techniques Cells Child Childhood Childhood Asthma Chromosomes Common Cold Coughing Data Development Disadvantaged Disease Epithelial Epithelial Cells Evaluation Exhibits Family member Genes Genetic Genetic Predisposition to Disease Genetic Risk Goals Human IL8 gene Immune Immune response Immunity Immunologics Immunology In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Intercellular adhesion molecule 1 Interferons Interleukin-6 Interleukin-8 Interleukins Investigation Knock-in Mouse Knowledge Laboratories Lead Link Literature Lung Lymphocyte Measures Mediator of activation protein Mus Mutation Nasal Epithelium New Mexico Nose Outcome Pathway interactions Patients Physiological Population Predisposition Regulation Research Resources Respiratory Signs and Symptoms Rhinovirus Rhinovirus infection Risk Role Shortness of Breath Single Nucleotide Polymorphism Slice Structure of parenchyma of lung Symptoms Syndrome System TSLP gene Testing Time Tissue Donors Tissues Universities Viral Viral Load result Virus Virus Diseases Wheezing Work acute symptom airway hyperresponsiveness airway inflammation antiviral immunity asthma exacerbation asthmatic base cytokine eosinophil gain of function high risk human tissue improved insight lung preservation neutrophil novel receptor response risk variant targeted treatment trafficking

项目摘要

PROJECT SUMMARY/ABSTRACT Asthma occurs in ~12% of the US population, and rhinovirus (RV) is recognized as the principal virus producing the common cold syndrome worldwide. Unlike patients without asthma who generally develop upper respiratory symptoms during colds, asthmatics with an RV infection exhibit severe lower respiratory symptoms (e.g., cough, wheeze, shortness of breath). In fact, RV, especially species A and C, are associated with 60% to 80% of asthma exacerbations in children requiring treatment in the emergency department. Recent literature has shown that mutations in cadherin-related family member 3 (CDHR3), the receptor for RVC, increases susceptibility to RVC infection during exacerbations of asthma. RVA viruses similarly lead to exacerbations of asthma; however, a genetic link to disease remains unclear. Single nucleotide polymorphisms (SNPs) in 17q21/ORM1-like 3 (ORMDL3) have been associated with both exacerbation and development of asthma. Strikingly, ~60% of individuals with childhood onset asthma will have risk alleles at this locus. Recently, ORMDL3 was shown to regulate intercellular adhesion molecule 1 (ICAM1) expression in A549 cells. ICAM1 is the receptor utilized by RVA to infect epithelial cells. Taken together, this proposal speculates that gain of function (GOF) SNPs in the 17q21/ORMDL3 locus (risk alleles) modulating ICAM1 expression underlie the genetic susceptibility to RVA exacerbations in those with asthma. Evaluation of this hypothesis will occur in two specific aims that maximize research strengths of the Kennedy Laboratory. For Aim 1, the Kennedy Laboratory will evaluate the effects of risk alleles on ICAM1 expression and downstream effects, including inflammatory cell infiltrates and mediators in children with asthma exacerbations. Aim 2 will focus on a novel human precision-cut lung slice (PCLS) platform from donors with asthma and risk alleles. Evaluations of ICAM1 expression and inflammatory mediators, as well as measures of airway hyper-responsiveness (AHR) to carbachol after RV16 infection in PCLS with and without risk alleles underlie this aim. It is understood that RV does not replicate well in murine systems and that human cell cultures lack the ability to investigate physiologic responses of tissue and host immunity during viral infections. With the Kennedy Laboratory’s ability to prepare and maintain PCLS from human donors that preserve lung architecture and physiologic responses, our laboratory can examine, within the correct host and target tissue, immunologic mechanisms driving AHR, a surrogate for asthma exacerbations, in lung tissue from donors with asthma and risk alleles during RVA infections ex vivo. The project described will generate important data about the immunology of RVA disease in high-risk asthma populations and will establish a framework on which to conduct further translational investigations into the relevance of 17q21/ORMDL3 risk alleles, ICAM1, and RVA-induced immune responses that trigger RVA-induced asthma exacerbations.

项目摘要/摘要哮喘发生在约12％的美国人群中，而鼻病毒（RV）被认为是主要病毒在世界范围内产生普通的冷综合症。与没有哮喘的患者通常发展上层感冒期间呼吸道症状，带有RV感染的哮喘患者表现出严重的下呼吸道症状（例如，咳嗽，喘息，呼吸急促）。实际上，RV，尤其是物种A和C，与60％相关在需要急诊科治疗的儿童中，有80％的哮喘患病患病。最近的文献已经表明，RVC的接收器中与钙粘蛋白相关的家族成员3（CDHR3）中的突变增加哮喘加重期间对RVC感染的敏感性。 RVA病毒类似地导致哮喘;但是，与疾病的遗传联系尚不清楚。单核苷酸多态性（SNP） 17q21/orm1样3（ORMDL3）与哮喘的加重和发展有关。令人惊讶的是，约60％的童年发作哮喘患者将在此基因座具有风险等位基因。最近，显示ORMDL3在A549细胞中调节细胞间粘合分子1（ICAM1）的表达。 ICAM1是 RVA使用的接收器可用于感染上皮细胞。综上所述，该提议推测了 17q21/ormdl3 locus（风险等位基因）中的函数（GOF）SNP调节ICAM1表达的基础患有哮喘患者的RVA加剧的遗传敏感性。对该假设的评估将在两个中发生具体目的是最大化肯尼迪实验室的研究优势。对于AIM 1，肯尼迪实验室将评估风险等位基因对ICAM1表达和下游影响的影响，包括炎症患有哮喘患儿童的细胞浸润和介质。 AIM 2将专注于新颖的人来自具有哮喘和风险等位基因的供体的精密切割肺切片（PCLS）平台。 ICAM1的评估表达和炎症介体，以及气道高反应性（AHR）的测量 RV16感染后的Carbachol在具有和没有风险等位基因的PCL中是该目标的基础。据了解RV 在鼠系统中不能很好地复制，并且人类细胞培养物缺乏研究生理的能力病毒感染期间组织和宿主免疫的反应。具有肯尼迪实验室准备的能力并维护保留肺建筑和生理反应的人类捐助者的PCL，我们实验室可以在正确的宿主和靶组织中检查驱动AHR的免疫机制在RVA期间，患有哮喘和风险等位基因的供体的肺组织中造成哮喘加重的代理感染离体。所描述的项目将生成有关RVA疾病免疫学的重要数据高风险的哮喘种群，并将建立一个框架，以进行进一步的翻译研究17q21/ORMDL3风险等位基因，ICAM1和RVA诱导的免疫反应的相关性这会触发RVA引起的哮喘加重。