Project 1 (Broide) will investigate innate pathways that contribute to airway inflammation and airway remodeling in asthma. This project will focus on increasing our understanding of how a novel innate cell cytokine (Folistatin Like Protein-1 or FSL-1) as well as a novel innate cell population of pro-inflammatory natural helper cells (NHC) (small mononuclear cells that express high levels of Th2 cytokines, but no markers for T cells, NK cells, mononuclear cells, macrophages, mast cells) mediate important aspects of allergen induced airway inflammation and remodeling. Studies will examine how allergen exposure in atopic asthma activates these two novel interconnected innate pathways to promote airway inflammation and remodeling (i.e. activation of natural helper cells to express Th2 cytokines that subsequently activate M2 macrophages to express FSL-1 a pro-inflammatory and pro-remodeling gene with receptors on smooth muscle and blood vessels). The importance of these novel innate pathways to asthma will be examined by studying levels of their expression in asthma compared to healthy controls, as well as in asthmatics challenged with allergen or rhinovirus. In addition we will determine the stimuli that induce their expression, the distribution of receptors that mediate their activation, and the profile of mediators released following their activation that are important to inflammation and remodeling. Finally, although the major focus of this project will be on studying human asthmatics, mouse models will be used to answer mechanistic questions that are not ethical to perform in humans (such as administration of anti-FSL-1 Ab, and adoptive transfer or depletion of NHC). This research project will interact with both Project 2 (Croft), Project 3 (Zuraw) and Core B to gain insight into how allergen and viral triggers of asthma contribute to airway inflammation and remodeling in asthma.

Public Health Relevance

Inhalation of airborne allergens such as cat and dust mite or respiratory viruses may result in damage and scarring of the bronchial tubes in susceptible asthmatics. This project will provide increased understanding of the cause of this scarring and suggest potential ways to identify asthmatics at risk for developing scarring of their lungs, or potential new treatments.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070535-09
Application #
8711191
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Das, Sudipta; Miller, Marina; Beppu, Andrew K et al. (2016) GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation. Proc Natl Acad Sci U S A 113:13132-13137
Mehta, Amit K; Duan, Wei; Doerner, Astrid M et al. (2016) Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33. J Allergy Clin Immunol 137:278-88.e6
Rajan, Jessica; Newbury, Robert O; Anilkumar, Arjun et al. (2016) Long-term assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids. J Allergy Clin Immunol 137:147-56.e8
Herro, Rana; Croft, Michael (2016) The control of tissue fibrosis by the inflammatory molecule LIGHT (TNF Superfamily member 14). Pharmacol Res 104:151-5
Zhou, Weisong; Toki, Shinji; Zhang, Jian et al. (2016) Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses. Am J Respir Crit Care Med 193:31-42
Mehta, Amit K; Gracias, Donald T; Croft, Michael (2016) TNF activity and T cells. Cytokine :
Rawson, Renee; Yang, Tom; Newbury, Robert O et al. (2016) TGF-β1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis. J Allergy Clin Immunol 138:791-800.e4
Miller, Marina; Esnault, Stephane; Kurten, Richard C et al. (2016) Segmental allergen challenge increases levels of airway follistatin-like 1 in patients with asthma. J Allergy Clin Immunol 138:596-599.e4
Karta, Maya R; Broide, David H; Doherty, Taylor A (2016) Insights into Group 2 Innate Lymphoid Cells in Human Airway Disease. Curr Allergy Asthma Rep 16:8
Kim, Alexander S; Doherty, Taylor A; Karta, Maya R et al. (2016) Regulatory B cells and T follicular helper cells are reduced in allergic rhinitis. J Allergy Clin Immunol 138:1192-1195.e5

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