The purpose of this proposal is to elucidate the mechanisms by which surfactant protein-A (SP-A) modulates inflammatory and immunologic responses in allergic asthma. We hypothesize that SP-A dysfunction leads to abnormal immunologic responses that contribute to the severity of allergic asthma. Three inter-related projects are proposed in this application, each of which is strengthened by studies in human subjects with asthma or the use of biologic specimens obtained from subjects with asthma. Therefore, we propose a Clinical and Laboratory Core to facilitate the safe and efficient collection of research data and specimens from human subjects. There are several advantages to such a facility. First, consolidating subject recruitment prevents duplication of personnel effort in each research project. Second, standardized subject assessment assures uniformity of experimental data across all projects in this program. Third, assembling an experienced clinical research team helps to maximize subject safety through the course of each research protocol. Finally, the consolidated laboratory facility allows for a uniform subject database and standardized collection and processing of biologic specimens for each project in this program.
In aim 1, we will recruit and screen approximately 140 subjects in years 1-4 to recruit 120 subjects (60 asthma, 60 normal) to participate in the bronchoscopy studies outlined in Project 1. We will also genotype and determine the epithelial permeability phenotype following ozone or filtered air exposure in Project 3.
In aim 2, 120 subjects (25/year) will undergo bronchoscopy in years 1-5 in Project 1 to obtain BAL fluid for purification of SP-A and airway epithellial cells for ex vivo experiments of SP-A function. Eighty subjects (16/year) will undergo bronchoscopy for studies outlined in Project 3. These subjects will be divided between the SP-A 223 polymorphism and epithelial permeability phenotype within the normal and asthmatic groups.
In aim 3 biologic specimens (bronchoalveolar lavage fluid and cells, endobronchial biopsies, and blood for DMA) obtained during the screening and bronchoscopy procedures will be processed and analyzed for use in Projects 1-3.
The presence of a Clinical and Laboratory Core is critical to the success of this proposal, as it will be utilized by all projects. It allows for efficient recruitment and screening of subjects, safe use of bronchoscopy by experienced personnel and an organized, consolidated approach to sample processing, sample use by each of the project and data management.
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