The overall goal of this program project is to establish the contributions of eosinophils (EOS) to allergic inflammation and pathophysiology of asthma by understanding the mechanisms leading to eosinophil priming, activation, adhesiveness, generation of chemokines to promote T cell recruitment and activation as well as stimulation of fibroblasts to produce collagen and other extracellulr matrix (ECM) proteins. It is our hypothesis that EOS play a pivotal role in asthma pathogenesis by enhancing airway inflammation and promoting airway remodeling via interactions with lymphocytes and fibroblasts rather than as primary effector cells of atopy. Our proposed studies in this Program Project application will first identify the mechanism(s) by which EOS amplify airway inflammation by generating T cell-active chemokines and enhancing T cell production of proinflammatory cytokines. Likewise, we propose that eosinophils enhance ECM generation by fibroblasts to promote airway remodeling (Project 1). Second, we will define the mechanisms of eosinophil adhesion and transmigration focusing on the interaction of alpha4beta1 integrin on EOS with its VCAM-1 ligand, the role of P-selectin in activation of beta1 integrin and the transient appearance of a structure known as the podosome, which promotes EOS adhesion (Project 2). Third, the molecular mechanisms by which EOS are """"""""primed"""""""" by IL-5 family cytokines will be studied with a focus on the role of intracellular signaling cascades (JAK-STAT and Ras- MAP kinase) in potentiating EOS responsiveness to chemokines (e.g. RANTES). The relationship of these signaling events to increased EOS adherence, migration, viability and release of proinflammatory or profibrotic mediators will be identified (Project 3). Fourth, to determine critically the mechanisms regulating the generation of the profibrotic cytokine, TGF-beta1, by EOS we will focus on the role of an isomerase, Pin-1, in stabilizing TGF-beta1 mRNA in EOS and mediating TGF-beta1 signaling in fibroblasts (Project 4). Studies will be performed at three levels: (1) cell function and cell-cell interaction;(2) intracellular signaling;and (3) gene expression and pre-/post-transcriptional control. We will test the hypotheses, generated from ex vivo experiments using blood EOS and cells obtained from the in vivo model of allergic airway inflammation that employs bronchoscopy with segmental bronchoprovocation with antigen at baseline as well as following treatment with the anti-IL-5 antibody. These projects will be facilitated by 3 cores (clinical, laboratory and administrative). From these collaborative and integrated approaches, we will directly address the role of EOS in allergic airway inflammation, and, as a consequence, determine novel and comprehensive insight into the mechanisms of EOS up-regulation and its role in airway disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL088594-05
Application #
8220773
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Noel, Patricia
Project Start
2008-02-01
Project End
2013-03-31
Budget Start
2012-02-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$2,080,220
Indirect Cost
$663,446
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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