The GPCR-CARMA3 Signaling Axis Mediates Inflammation in Asthma
Abstract
This application will address the research topic area of Respiratory Health; specifically, the project will focus on the cause and treatment of respiratory symptoms associated with asthma. Asthma is a common lung disease in both the general and military populations. Despite the widespread availability of drug therapy, more than half of the 300 million people worldwide with asthma have inadequate control of their symptoms resulting in an increased risk of flares and high costs to both the military and the United States in general. In addition, current therapies require chronic use and have significant safety concerns. More effective therapies are clearly needed and will best be identified by increasing our understanding of how asthma develops. Recently it has been recognized that the cells lining the airways in the lungs play a critical role in the development of asthma. These cells not only serve as a barrier that helps protect the lung, but they also sense and orchestrate the body s response to inhaled infectious agents and toxins. However, if the airway lining cells inappropriately react to a relatively harmless inhaled substance (e.g., cat dander), this can result in inflammation and the symptoms of asthma. One of the earliest steps in the process is stimulation of the airway lining cells to release mediators that induce inflammation of the airways and ultimately cause the symptoms of asthma. It follows that understanding the mechanisms by which airway lining cells contribute to the development of asthma should help identify novel targets for therapy. Engagement of specialized receptors on airway lining cells by inhaled substances can stimulate the cells to induce the production of inflammatory mediators via activation of specialized signaling pathways in the cells. Importantly these mediators are upregulated in the airways of people with asthma (asthmatics) in response to allergic stimuli, and the signaling pathways activated have been shown to be critical for the development of asthma in both human studies and in mouse models of asthma. However, these signaling pathways have been difficult to target with drugs and a more narrow approach is needed. A cell protein called CARMA3 has been shown to have a special role organizing signaling pathways in airway lining cells. We have demonstrated that CARMA3 links activation of the airway lining cells to the activation of the immune system in the lung. In addition, we have recently shown that CARMA3 in the airway lining is critical for initiation of asthma. We now have preliminary data showing that CARMA3 mediates key signaling pathways in these cells and is also necessary for the development of airway inflammation in a model of severe asthma. It follows that targeting CARMA3 in the airway lining could prevent the development of asthma and asthma exacerbations. For this application, we propose that the immune response in asthma is controlled through CARMA3 and that targeting this signaling axis could interrupt the earliest steps in the establishment and exacerbation of asthma. This project will utilize animal modeling, human studies, and novel mechanistic screens to determine the signaling mechanisms of CARMA3 and if targeting CARMA3 in the airway lining is a viable therapy for asthma. Results from this proposal will (i) determine how CARMA3 activity controls immune responses in mouse models and human subjects with asthma, (ii) identify molecular mechanisms driving CARMA3 signaling, and (iii) reveal potential therapeutic targets that utilize the CARMA3 signaling network.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610493
Entities
People
- Benjamin D Medoff
Organizations
- Massachusetts General Hospital
- United States Army