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.

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL088594-07
Application #
8646957
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
Wilkerson, Emily M; Johansson, Mats W; Hebert, Alexander S et al. (2016) The Peripheral Blood Eosinophil Proteome. J Proteome Res 15:1524-33
Shen, Zhong-Jian; Hu, Jie; Shiizaki, Kazuhiro et al. (2016) Phosphate-Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1. PLoS One 11:e0150093
Esnault, Stephane; Johansson, Mats W; Kelly, Elizabeth A et al. (2016) IL-3 Up-regulates and Activates Human Eosinophil CD32 and αMß2 Integrin Causing Degranulation. Clin Exp Allergy :
Olson, Ashleigh A; Evans, Michael D; Johansson, Mats W et al. (2016) Role of food and aeroallergen sensitization in eosinophilic esophagitis in adults. Ann Allergy Asthma Immunol 117:387-393.e2
Mathur, Sameer K; Fichtinger, Paul S; Evans, Michael D et al. (2016) Variability of blood eosinophil count as an asthma biomarker. Ann Allergy Asthma Immunol 117:551-553
Esnault, Stephane; Kelly, Elizabeth A; Sorkness, Ronald L et al. (2016) Airway factor XIII associates with type 2 inflammation and airway obstruction in asthmatic patients. J Allergy Clin Immunol 137:767-73.e6
Zheng, M; Turton, K B; Zhu, F et al. (2016) A mix of S and ΔS variants of STAT3 enable survival of activated B-cell-like diffuse large B-cell lymphoma cells in culture. Oncogenesis 4:e184
Kelly, Elizabeth A; Esnault, Stephane; Johnson, Sean H et al. (2016) Human eosinophil activin A synthesis and mRNA stabilization are induced by the combination of IL-3 plus TNF. Immunol Cell Biol 94:701-8
Metcalfe, Dean D; Pawankar, Ruby; Ackerman, Steven J et al. (2016) Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases. World Allergy Organ J 9:7
Shen, Zhong-Jian; Malter, James S (2015) XBP1, a determinant of the eosinophil lineage. Nat Immunol 16:793-4

Showing the most recent 10 out of 79 publications