Pulmonary Surfactant Antagonists of Rhinovirus Infection and Inflammation

鼻病毒感染和炎症的肺表面活性剂拮抗剂

• 批准号: 9359965
• 负责人: DENNIS R. VOELKER
• 金额: $ 38.77万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9359965
• 关键词: Address; Adult; Affect; Asthma; Attenuated; Automobile Driving; Biometry; Biostatistics Core; CD4 Positive T Lymphocytes; Cadherins; Cell Culture Techniques; Cells; Child; Childhood; Childhood Asthma; Clinical; Control Groups; Coupled; Data; Disease; Dose; Economic Burden; Effectiveness; Elements; Emergency department visit; Environmental Exposure; Epigenetic Process; Epithelial; Epithelial Cells; Family member; Genes; Genetic Heterogeneity; Hospitalization; Human; Immunization; Infection; Infection prevention; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Investigation; Lead; Lipids; Low Density Lipoprotein Receptor; Modeling; Molecular; Morbidity - disease rate; Mus; Nasal Epithelium; Nose; Outcome; Patient-Focused Outcomes; Patients; Phenotype; Phosphatidylglycerols; Phosphatidylinositols; Phospholipids; Population; Predisposing Factor; Primary Infection; Production; Property; Protein Isoforms; Proteins; Public Health; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Pyroglyphidae; Recording of previous events; Refractory; Regulation; Research Project Grants; Research Proposals; Resistance; Respiratory physiology; Rhinovirus; Route; Serotyping; Signal Transduction; Techniques; Testing; Therapeutic; Viral; Viral Physiology; Virus; Virus Diseases; Virus Replication; Work; airway inflammation; analog; asthmatic; cohort; efficacy testing; in vivo; inhibitor/antagonist; injured airway; minimally invasive; molecular phenotype; mortality; mouse model; novel; novel strategies; pediatric patients; prevent; receptor; response; surfactant; transcriptomics

Viral exacerbations of asthma are responsible for 1.8 million emergency room visits and 0.4 million hospitalizations in the US each year, constituting a major public health problem and economic burden. Human rhinoviruses (HRV) are the dominant instigators of asthma exacerbations in children and adults. Currently, there are not preventives or therapeutics for HRV infection. Our recent work has identified three constituents of human pulmonary surfactant, the phospholipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), and surfactant protein A (SP-A), as potent inhibitors of HRV infection and inflammatory sequelae. This proposal is focused upon defining how POPG, PI and SP-A inhibit viral infection in primary cultures of human nasal epithelial cells; and testing the efficacy of these agents for preventing exacerbations in mouse models of asthma. We will address these issues in three Specific Aims. In Aim 1 we will investigate the molecular mechanisms of human SP-A inhibition of 3 types of HRV infection with special emphasis upon the isoforms of the protein that are most effective against each virus. We will examine the anti-viral activities of the three major expressed isoforms of human SP-A encoded by the SP-A1 gene, and the three major expressed isoforms encoded by the SP-A2 gene. In Aim 2 we will investigate the mechanisms of POPG and PI inhibition of three types of HRV infection and inflammation. In Aim 3 we will critically test the activities of PI and novel structural anaolgs of the lipid as inhibitors of HRV infection in mice. PI and structural analogs will also be examined for their activity as suppressors of asthma exacerbations, using a house dust mite model for asthma coupled with HRV infection in mice. The studies in this project will be integrated with 3 other Research Projects, a Clinical Core and a Biostatistics/Environmental Exposure Core that are essential elements of the entire Research Proposal. The Clinical Core will provide patient nasal epithelial cells from exacerbation-prone asthmatics and multiple control groups. Project 1 will provide detailed information regarding the environmental exposures that drive asthma exacerbations and influence the phenotypes of the epithelial cells, and ultimately the clinical outcome of patients. We will interface with Project 2 by determining how SP-A, POPG, PI and lipid analog antagonism of HRV infection influences the transcriptomic profiles of the epithelial cells and if there are any associations with environmental exposures and clinical outcomes. Our interactions with Project 3 will focus upon how the interactions between SP-A and lipids influence the production and secretion of factors from nasal epithelial cells that influence the epigenetic landscape and phenotypes of CD4+ T cells. In total, Project 4 will provide new information about the anti-viral properties of pulmonary surfactant constituents and their utility for preventing HRV-dependent asthma exacerbations in the context of known environmental exposures and nasal epithelial phenotypes.

哮喘的病毒加重负责180万急诊室访问和40万 每年在美国的住院，构成了一个重大的公共卫生问题和经济负担。 人类鼻病毒（HRV）是儿童和成人哮喘恶化的主要煽动者。 目前，没有预防性或HRV感染的治疗剂。我们最近的工作已经确定了三个 人肺表面活性剂，磷脂，棕榈酰 - 烯酰基磷脂酰甘油（POPG）的成分 和磷脂酰肌醇（PI）和表面活性剂蛋白A（SP-A），作为HRV感染的有效抑制剂和 炎症后遗症。该建议的重点是定义POPG，PI和SP-A如何抑制病毒感染 在人鼻上皮细胞的原发性培养中；并测试这些试剂的疗效 哮喘小鼠模型中的加重。我们将以三个具体目标解决这些问题。在目标1中 我们将研究人类SP-A抑制3种类型的HRV感染的分子机制 强调对每种病毒最有效的蛋白质的同工型。我们将检查 SP-A1基因编码的三个主要表达人类SPA的同工型的抗病毒活性， 由SP-A2基因编码的三个主要表达同工型。在AIM 2中，我们将研究 POPG和PI抑制了三种类型的HRV感染和炎症。在AIM 3中，我们将严格测试 PI和新型脂质的新结构Anaolgs作为小鼠HRV感染的抑制剂的活性。 PI和结构 还将检查类似物的活动作为哮喘加重的抑制器的活动，并使用房屋灰尘 哮喘的螨模型与小鼠中的HRV感染结合。该项目中的研究将与3集成 其他研究项目，临床核心和生物统计学/环境暴露核心，这是必不可少的 整个研究建议的要素。临床核心将提供患者的鼻中皮细胞 恶化且容易发生的哮喘患者和多个对照组。项目1将提供详细信息 关于驱动哮喘加重并影响表型的环境暴露 上皮细胞，最终是患者的临床结果。我们将通过确定项目2与项目2进行交互 HRV感染的SP-A，POPG，PI和脂质模拟拮抗作用如何影响 上皮细胞以及是否与环境暴露和临床结果有任何关联。我们的 与项目3的互动将集中于SP-A和脂质之间的相互作用如何影响 影响表观遗传景观和 CD4+ T细胞的表型。总共，项目4将提供有关抗病毒特性的新信息 肺表面活性剂成分及其对预防HRV依赖性哮喘恶化的实用性 已知的环境暴露和鼻上皮表型的背景。