Role of the Leukotriene E4 Receptor GPR99 in Asthma
Abstract
Bronchial asthma is a chronic (long-term) inflammatory disease of the airways that causes periodic attacks of coughing, wheezing, shortness of breath, and chest tightness. Asthma can be induced and worsened by infections, allergens, and irritant chemicals used in military operations and chemical warfare. The prevalence of asthma in military Veterans has increased during the last decade. Therefore, advancements in understanding mechanisms of asthma are essential to the disease therapy and the respiratory health of military members. Leukotrienes are one of the substances that can be made inside the body by various stimuli and are involved in asthma. There are three different leukotrienes: leukotriene C4 (LTC4), LTD4, and LTE4. Biological actions of those leukotrienes start with the binding to their respective counterparts called “receptors.” Accordingly, there are three different receptors: type 1 (CysLT1R, recognizing LTD4) and type 2 (CysLT2R, recognizing LTC4) receptors and the newly found receptor called GPR99 that recognize LTE4. CysLT1R and CysLT2R are located on airway smooth muscle, and the drugs that block the LTD4 binding to CysLT1R, such as SINGULAIR®, have proven benefit in asthma, but some patients do not respond to the drug. GPR99 is located on cells lining the surface of airways (epithelial cells), and LTE4 binding on GPR99 promotes mucus production, which is a risk factor of severe asthma. This proposal is to understand how GPR99 controls mucus production and mucus-producing cell development and to determine how GPR99 further regulates inflammatory responses underlying in asthmatic airways. Various mouse models with mouse strains that genetically lack GPR99 or other receptors will be used for that purpose. Thus, this proposal will test the possibility that GPR99 can be a new target for treatment of asthma and is consistent with the program mission to improve Respiratory Health.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710527
Entities
People
- Yoshihide Kanaoka
Organizations
- United States Army