The purpose of this Asthma and Allergic Diseases Cooperative Research Center (AADCRC) proposal is to elucidate the mechanisms by which the innate immune system affords protection against exuberant type 2 inflammation and exacerbations in asthma. This will be done by evaluating three separate but related innate immune mediators: surfactant protein-A (SP-A), the lipid portion of surfactant, palmitoyl-oleoyl- phosphatidylglycerol (POPG) and Toll interacting protein (Tollip), an innate immune mediator known to cross talk with SP-A and POPG. Each of these mediators modulates inflammatory and immunologic responses in asthma. The impact of each of these projects in the AADCRC program is enhanced by the translation of observations made in animal models to studies in human subjects with asthma and/or the use of biologic airway and systemic specimen samples obtained from subjects with asthma. This core will serve all the projects so that the central hypothesis can be tested: We hypothesize that dysfunction of SP-A, Tollip and POPG occurs as a consequence of genetic polymorphisms and degradative events which significantly alter their function in the setting of asthma and viral infection, leading to exacerbations and persistence of inflammation. Replacement of functional surfactant protein-A (SP-A) and POPG offer novel alternatives to correct this dysfunction, attenuate type 2 inflammation and reduce exacerbations. The Clinical Core will provide the expertise and organization necessary to facilitate the safe and efficient collection of research data and assure consistent processing, distribution and storage of clinical specimens to the research investigators. The Clinical Core will be responsible for recruitment, screening, and characterization of approximately 250 participants with asthma such as 100 subjects with asthma (50 mild, 50 severe) and 50 normal participants will engage in the studies outlined in Projects 1-3, which include bronchoscopy. The bronchoscopies will be performed by Clinical Core personnel who have a superb safety record of performance and significant experience. Also included is a Biostatistical Unit who will be conducting the data management and statistical analysis for the U19 program. In addition to providing each Project with genotyping and phenotyping information on each enrolled participant, the Clinical Core will provide Projects 1, 2 and 3 with bronchoalveolar lavage (BAL) fluid, nasal and bronchial epithelial cells and SP-A extracted from BAL. For Projects 1 and 2, the Core will also provide endobronchial biopsies and Project 2 will receive BAL macrophages. In this capacity, the Core will allow each clinical sample to be utilized to its full potential, and serve all projects we equally. For all of the studies within the AADCRC utilizing human subject samples, the Clinical Core will also be responsible for assuring patient safety, data confidentiality and full regulatory compliance. The Core will also be responsible for sample storage and shipping of samples in coordination with the administrative core to achieve the goals of the AADCRC program.
