Asthma can manifest with varying levels of severity. Whereas the acute phase of mild and moderate asthma is characterized largely by rapid infiltration of a number of cell types within the lungs, such as T lymphocytes, eosinophils, and mast cells, severe asthma has additional features that are thought to strongly contribute to decline in lung function. These include airway epithelial cell mucus metaplasia, smooth muscle hypertrophy or hyperplasia, subepithelial fibrosis, and increased angiogenesis. Fibrosis is due to deposition of extracellular matrix proteins such as collagen, fibronectin, tenascin, and laminin, thought to be produced largely by differentiating fibroblasts or epithelial cells. These structural cells can additionally be induced to express alpha smooth muscle actin and may contribute to increased rigidity of the airways together with proliferation or hypertrophy of mature smooth muscle cells that line the bronchioles. The inflammatory factors that control all of these cell types are then likely to be important in severe asthma. This proposal will focus on several members of the tumor necrosis factor (TNF) and TNF receptor superfamily, and test the hypotheses that LIGHT (TNFSF14) interacting with its two receptors HVEM (TNFRSF14) and LT?R (TNFRSF3), and TL1A (TNFSF15) interacting with its receptor DR3 (TNFRSF25), are central mediators and drivers of the fibrotic and remodeling activities of lung epithelial cells, lung fibroblasts, and airway smooth muscle cells. The treatment options for asthmatics are currently limited. Understanding when and where these TNF/TNFR family molecules are expressed, and the functional response that is elicited from their interactions, might lead to new and novel targets for therapeutic intervention in severe asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070535-15
Application #
9993182
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2006-09-01
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
15
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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