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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.

项目总结/摘要哮喘发生在约12%的美国人口，鼻病毒（RV）被认为是主要的病毒在世界范围内引起普通感冒综合症。不像没有哮喘的患者，呼吸道症状在感冒期间，RV感染的哮喘患者表现出严重的下呼吸道症状 (e.g.,咳嗽、喘鸣、呼吸急促）。事实上，RV，特别是A和C种，与60%至60%的 80%的儿童哮喘急性发作需要在急诊室接受治疗。最近的文献研究表明，钙粘蛋白相关家族成员3（CDHR 3）（RVC的受体）的突变，哮喘急性发作期间RVC感染的易感性。RVA病毒类似地导致哮喘;然而，与疾病的遗传联系仍不清楚。单核苷酸多态性（SNPs） 17 q21/ORM 1-like 3（ORMDL 3）基因与哮喘的发生、发展和加重有关。引人注目的是，约60%的儿童期发作哮喘患者在该基因座上具有风险等位基因。最近， ORMDL 3可调节A549细胞中细胞间粘附分子1（ICAM 1）的表达。ICAM 1是 RVA用来感染上皮细胞的受体。总的来说，这一提议推测， 17 q21/ORMDL 3基因座中调节ICAM 1表达的GOF单核苷酸多态性（风险等位基因）是ICAM 1表达的基础。哮喘患者对RVA加重的遗传易感性。对这一假设的评估将在两个最大限度地发挥肯尼迪实验室的研究优势的具体目标。目标1：肯尼迪实验室将评估风险等位基因对ICAM 1表达和下游效应的影响，包括炎症反应，细胞浸润和介质在儿童哮喘急性发作中的作用目标2将集中在一个新的人类精确切割肺切片（PCLS）平台，来自患有哮喘和风险等位基因的供体。ICAM 1的评价表达和炎症介质，以及气道高反应性（AHR）的措施， RV 16感染PCLS后的卡巴胆碱与和无风险等位基因的基础这一目标。据了解，RV 在小鼠系统中不能很好地复制，并且人细胞培养物缺乏研究生理学特性的能力。病毒感染期间组织和宿主免疫的反应。肯尼迪实验室有能力并维持来自人类供体的PCLS，以保持肺结构和生理反应，我们实验室可以检查，在正确的宿主和靶组织，免疫机制驱动AHR，哮喘急性发作的替代物，在RVA期间来自患有哮喘和风险等位基因的供体的肺组织中离体感染。所描述的项目将产生关于RVA疾病免疫学的重要数据，高危哮喘人群，并将建立一个框架，在此基础上进行进一步的翻译 17 q21/ORMDL 3风险等位基因、ICAM 1和RVA诱导的免疫应答的相关性研究引发RVA诱发的哮喘恶化