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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

基本信息

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
项目类别：
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

项目摘要

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.

由病毒引起的哮喘恶化导致180万急诊室就诊和40万急诊室就诊