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: 10246164
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246164
• 关键词: Address; Adult; Affect; Antiviral Agents; 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; Molecular; Morbidity - disease rate; Mus; Nasal Epithelium; 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; Rhinovirus; Rhinovirus infection; Route; Serotyping; Signal Transduction; Structure; Techniques; Testing; Therapeutic; Viral; Viral Physiology; Virus; Virus Diseases; Virus Replication; Work; airway inflammation; analog; asthma exacerbation; asthma model; asthmatic; bronchial epithelium; cohort; efficacy testing; in vivo; inhibitor/antagonist; injured airway; minimally invasive; molecular phenotype; mortality; mouse model; novel; novel strategies; pediatric patients; prevent; pulmonary function decline; 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.

病毒性哮喘急性发作导致180万急诊室就诊和40万 美国每年的住院人数约为100万，构成了一个主要的公共卫生问题和经济负担。 人鼻病毒（HRV）是儿童和成人哮喘急性发作的主要诱因。 目前，没有针对HRV感染的预防或治疗药物。我们最近的工作已经确定了三个 人肺表面活性物质的成分，磷脂，棕榈酰-油酰-磷脂酰甘油（POPG） 和磷脂酰肌醇（PI）和表面活性蛋白A（SP-A），作为HRV感染的有效抑制剂， 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代培养物中;以及测试这些试剂用于预防 小鼠哮喘模型中的急性加重。我们将在三个具体目标中解决这些问题。目标1 我们将研究人SP-A抑制3种类型HRV感染的分子机制， 强调对每种病毒最有效的蛋白质同种型。我们会研究 由SP-A1基因编码的人SP-A的三种主要表达同种型的抗病毒活性，以及 由SP-A2基因编码的三种主要表达同种型。在目标2中，我们将研究 POPG和PI抑制三种类型的HRV感染和炎症。在目标3中，我们将严格测试 PI的活性和脂质的新结构类似物作为小鼠中HRV感染的抑制剂。PI和结构 类似物也将被检查其作为哮喘恶化抑制剂的活性，使用屋尘 螨性哮喘合并HRV感染小鼠模型。该项目的研究将与3 其他研究项目，临床核心和生物统计/环境暴露核心是必不可少的 这是整个研究计划的一部分。临床核心将提供患者鼻上皮细胞， 易加重哮喘患者和多个对照组。项目1将提供详细信息 关于驱动哮喘恶化和影响哮喘患者表型的环境暴露， 上皮细胞，并最终影响患者的临床结果。我们将与项目2进行对接， HRV感染的SP-A、POPG、PI和脂质类似物拮抗作用如何影响 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 与项目3的相互作用将重点关注SP-A和脂质之间的相互作用如何影响 鼻上皮细胞产生和分泌影响表观遗传景观的因子， CD 4 + T细胞的表型。总的来说，项目4将提供关于抗病毒特性的新信息， 肺表面活性物质成分及其在预防HRV依赖性哮喘急性发作中的应用 已知环境暴露和鼻上皮表型的背景。