The role of the cardiac protein alpha-T-catenin in the pathogenesis of toluene-diisocyanate-induced asthma

Project: Research project

Description

About 10-25% of adult asthma is occupation-induced, a subtype defined by the exposure of environmental irritants to susceptible individuals. Recently, a genome-wide association study, with subsequent independent replication, has shown that mutations in alpha-T-catenin correlate with both the incidence and severity of toluene diisocyanate (TDI) induced asthma, the most common identified cause of occupational asthma. How alpha-T-catenin, a protein primarily found in heart and a component of cadherin-based intercellular junctions, contributes to the pathogenesis of TDI-asthma is unknown. The goals of this project are to identify the primary alpha-T-catenin-expressing lung cell type and determine how it affects the severity of TDI-induced asthma in a murine model. Alpha-T-catenin was found present in cardiomyocytes surrounding pulmonary veins (PV), and alpha-T-catenin KO PVs show an increase in size of the cardiomyocyte sheath, an effect that is proportionally similar to the established increase in heart size observed in alpha-T-catenin KO mice. When exposed to TDI in an asthma model, the alpha-T-catenin KO mice developed an decreased airway hyperresponsivity, with lower reactivity to methacholine challenges when compared to wild-type littermate controls using enhanced pause (Penh) measurements via plethysmography. Interestingly, the vehicle-only control baseline Penh in KO mice was significantly higher than that of wild-type. Additionally, there was no significant differences in airway inflammation as examined by BAL However, the mechanism by which alpha-T-catenin loss alters lung function is not known. Since we could not detect a difference in airway inflammation, alpha-T-catenin loss may induce vascular dysfunction to contribute to the pathogenesis of TDI-asthma. This has the potential to be become a paradigm-shift away from the airway-centric research surrounding occupational asthma.
StatusFinished
Effective start/end date1/1/158/31/15

Funding

  • American Heart Association Midwest Affiliate (15PRE21850010)

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Toluene 2,4-Diisocyanate
alpha Catenin
Asthma
Proteins
Occupational Asthma
Cardiac Myocytes
Inflammation
Dimercaprol
Catenins
Lung
Intercellular Junctions
Plethysmography
Methacholine Chloride
Pulmonary Veins
Irritants
Genome-Wide Association Study
Environmental Exposure
Cadherins
Occupations
Blood Vessels