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.

哮喘病毒性恶化导致 180 万人次到急诊室就诊，40 万人次就诊 美国每年都有人住院，构成重大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诱因。 目前，尚无 HRV 感染的预防或治疗方法。我们最近的工作确定了三个 人肺表面活性剂、磷脂、棕榈酰油酰磷脂酰甘油 (POPG) 的成分 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。该提案的重点是定义 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；并测试这些药物预防的功效 小鼠哮喘模型的恶化。我们将通过三个具体目标来解决这些问题。目标 1 我们将通过特殊的方法研究人SP-A抑制3种HRV感染的分子机制 强调对每种病毒最有效的蛋白质亚型。我们将检查 由 SP-A1 基因编码的三种主要表达的人 SP-A 亚型的抗病毒活性，以及 SP-A2 基因编码的三种主要表达亚型。在目标 2 中，我们将研究以下机制： 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 的活性以及该脂质的新型结构模拟物作为小鼠 HRV 感染抑制剂的活性。 PI和结构 还将使用室内灰尘检查类似物作为哮喘恶化抑制剂的活性 小鼠哮喘与 HRV 感染相结合的螨模型。该项目的研究将与 3 其他重要的研究项目、临床核心和生物统计学/环境暴露核心 整个研究计划的要素。临床核心将为患者提供来自 易恶化的哮喘患者和多个对照组。项目1将提供详细信息 关于导致哮喘恶化并影响哮喘表型的环境暴露 上皮细胞，最终影响患者的临床结果。我们将通过确定与项目 2 交互 SP-A、POPG、PI 和 HRV 感染的脂质类似物拮抗作用如何影响 HRV 的转录组谱 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 CD4+ T 细胞的表型。总的来说，项目 4 将提供有关抗病毒特性的新信息 肺表面活性物质成分及其预防 HRV 依赖性哮喘恶化的效用 已知环境暴露和鼻上皮表型的背景。