Trafficking of eosinophils from the bone marrow to tissues may contribute to tissue damage and remodeling which are features of chronic allergic inflammation in human subjects with severe ongoing allergic inflammation. The mechanism and consequence of eosinophil trafficking to tissues is difficult to study in human subjects. We have therefore developed a novel mouse model of sustained eosinophil trafficking from bone marrow to tissues in response to repetitive allergen challenge which is a model that shares many features with ongoing allergic inflammation in humans. We propose to use this novel mouse model to investigate how eosinophils traffic in angiogenic vesselsat sites of allergic inflammation, and once in the tissues contribute to angiogenesis and fibrosis.
Specific aims#1 and #2 will focus on studying the interaction of eosinophils with endothelium in angiogenic vessels in a skin chamber model which allows direct visualization of fluorescently labeled eosinophils in bloodvessels in the skin chamber. Eosinophil adhesion in angiogenic vessels and vascular permeability changes will be quantitated in mice treated with neutralizing Abs to VEGF and other angiogenic cytokines identified to be expressed at sites of ongoing allergic inflammation.
In specific aims #3 and #4, we propose to determine the contribution of different isoforms of TGF-beta derived from eosinophils to tissue fibrosis, as well as the importance of fibroblast progenitor trafficking from the bone marrow tissue to tissue fibrosis. Overall these studies will help to determine the role of ongoing allergic inflammation to blood vesseland tissue changes which result in persistent tissue swelling and scarring at sites of ongoing allergic inflammation. These studies may identify potential therapeutic targets which can reduce the tissuedamage and swelling at sites of ongoing allergic inflammation in human subjects with severe ongoing allergies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI038425-12
Application #
7328621
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Plaut, Marshall
Project Start
1996-04-01
Project End
2011-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
12
Fiscal Year
2008
Total Cost
$341,020
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chen, Jun; Miller, Marina; Unno, Hirotoshi et al. (2018) Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma. J Allergy Clin Immunol 142:207-218.e6
Karta, Maya R; Rosenthal, Peter S; Beppu, Andrew et al. (2018) ?2 integrins rather than ?1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung. J Allergy Clin Immunol 141:329-338.e12
Doherty, Taylor A; Broide, David H (2018) Lipid regulation of group 2 innate lymphoid cell function: Moving beyond epithelial cytokines. J Allergy Clin Immunol 141:1587-1589
Unno, Hirotoshi; Miller, Marina; Rosenthal, Peter et al. (2018) Activating transcription factor 6? (ATF6?) regulates airway hyperreactivity, smooth muscle proliferation, and contractility. J Allergy Clin Immunol 141:439-442.e4
Miller, Marina; Vuong, Christine; Garcia, Meghan Farrell et al. (2018) Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? J Allergy Clin Immunol 142:706-709.e4
Miller, Marina; Rosenthal, Peter; Beppu, Andrew et al. (2017) Oroscomucoid like protein 3 (ORMDL3) transgenic mice have reduced levels of sphingolipids including sphingosine-1-phosphate and ceramide. J Allergy Clin Immunol 139:1373-1376.e4
Song, Dae Jin; Miller, Marina; Beppu, Andrew et al. (2017) Rhinovirus Infection of ORMDL3 Transgenic Mice Is Associated with Reduced Rhinovirus Viral Load and Airway Inflammation. J Immunol 199:2215-2224
Eastman, Jacqueline J; Cavagnero, Kellen J; Deconde, Adam S et al. (2017) Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 140:101-108.e3
Lund, Sean J; Portillo, Alex; Cavagnero, Kellen et al. (2017) Leukotriene C4 Potentiates IL-33-Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation. J Immunol 199:1096-1104
Miller, Marina; Tam, Arvin B; Mueller, James L et al. (2017) Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate. J Immunol 198:3017-3022

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