The overarching goal of this proposal is to define the mechanisms by which airway exposure to allergic stimuli primes peripheral blood eosinophils (EOS) to attach and extravasate into tlie lung to become effector cells contributing to the regulation of lymphocytes and fibroblasts thus contributing to ainway inflammation and remodeling in asthma. We propose that IL-3 stimulation of EOS contributes to Th17 lymphocyte development through EOS release of IL-1 p and production of factors relevant to tissue remodeling (Project 1). IL-3-stimulated EOS-derived production of semaphorin7A is hypothesized to activate fibroblasts to produce extracellular matrix (EClVI) components (Project 1). One of these components, periostin, may direct further recruitment of EOS from the blood to the airway (Project 2). Finally, airway ECM production is also regulated by EOS-secreted TGF-pi via signaling mechanisms involving the cis-trans peptidyl-prolyl isomerase, Pin1 (Project 3). Mechanistic studies with peripheral blood EOS can be validated in vivo using the segmental allergen challenge model. The significance of the proposed research is that each project will contribute to the understanding of EOS biology in the asthmatic airway, potentially identifying several new drug targets that could modify the process of lung remodeling. To accomplish this and provide service to the projects. Core A is divided into the following Tasks: Specific Task 1 - To recruit and characterize allergic asthma subjects for participation in experimental protocols involving peripheral blood and airway EOS; Specific Tasl< 2 - To perform phlebotomy 4 days a week for the purification of peripheral blood EOS from patients with allergies or allergic asthma; Specific Tasl< 3 - To perform bronchoscopies with segmental bronchoprovocation with allergen (Ag-SBP) in subjects with asthma and obtain BAL fluid and endobronchial biopsies (Bx) before and after allergen challenge; Specific Task 4 - To perform basic processing and laboratory analysis of airway and blood samples that are not part of Core B, including immunohistochemistry, establishing fibroblasts cell lines from endobronchial Bx; and Specific Task 5 - To maintain high-quality HIPAA-compliant databases that includes subject demographic, clinical and physiologic characteristics, safety data, and basic BAL analysis, in addition to providing assistance in data retrieval, analysis, and presentation and to provide statistical support for all projects.
Given the central importance of EOS in the progression of asthma severity, this proposal will allow for a better understanding ofthe molecular basis of ainway remodeling and begin to develop a risl< signature that could be used for early detection of lung function decline. The ability to study newly recruited and activated ainway EOS in response to segmental allergen challenge maximally facilitates discovery translation.
| Moon, Hyung-Geun; Kim, Seung-Jae; Jeong, Jong Jin et al. (2018) Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization. Immunity 49:275-287.e5 |
| Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83 |
| Johansson, Mats W; Kelly, Elizabeth A; Nguyen, Christopher L et al. (2018) Characterization of Siglec-8 Expression on Lavage Cells after Segmental Lung Allergen Challenge. Int Arch Allergy Immunol 177:16-28 |
| Evans, Michael D; Esnault, Stephane; Denlinger, Loren C et al. (2018) Sputum cell IL-1 receptor expression level is a marker of airway neutrophilia and airflow obstruction in asthmatic patients. J Allergy Clin Immunol 142:415-423 |
| Esnault, Stephane; Hebert, Alexander S; Jarjour, Nizar N et al. (2018) Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3. J Proteome Res 17:2102-2111 |
| Bortnov, Valeriu; Annis, Douglas S; Fogerty, Frances J et al. (2018) Myeloid-derived growth factor is a resident endoplasmic reticulum protein. J Biol Chem 293:13166-13175 |
| Schwantes, Elizabeth A; Evans, Michael D; Cuskey, Alex et al. (2018) Elevated fractional exhaled nitric oxide and blood eosinophil counts are associated with a 17q21 asthma risk allele in adult subjects. J Asthma Allergy 11:1-9 |
| Tomasini-Johansson, Bianca R; Mosher, Deane F (2018) Microtiter assays for quantitation of assembly of plasma and cellular fibronectin. Methods Cell Biol 143:157-170 |
| Turton, Keren B; Wilkerson, Emily M; Hebert, Alex S et al. (2018) Expression of novel ""LOCGEF"" isoforms of ARHGEF18 in eosinophils. J Leukoc Biol 104:135-145 |
| Bernau, Ksenija; Leet, Jonathan P; Esnault, Stephane et al. (2018) Eosinophil-degranulation products drive a proinflammatory fibroblast phenotype. J Allergy Clin Immunol 142:1360-1363.e3 |
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