An Alternative Pathobiology underlying Severe Asthma
NIH
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Project Abstract This application is for a Mentored Patient-Oriented Research Career Development Award entitled “An Alternative Pathobiology underlying Severe Asthma.” I am an Assistant Professor of Medicine at the University of Pittsburgh seeking additional training in benchtop murine research techniques and bioinformatics and ‘omics analysis to transition from benchtop to translational asthma research. The focus of my research is on the role of Type-1 (T1) inflammation in asthma and how this pathway may contribute to disease severity. While great strides have been made in understanding and treating traditionally described Type-2 (T2) inflammation in asthma with novel biologic therapies, nearly 50% of asthma patients lack evidence of this pathway, and even some with T2 inflammation fail to respond well to T2 therapies. A better understanding of other inflammatory pathways in asthma and how they contribute to disease is essential to identifying novel therapeutics for these patients. My preliminary data have demonstrated the presence of T1 inflammation marked by increased expression of IFN-γ, the chemokines CXCL10 and CCL5 as well as T1 expressing tissue resident memory T-cells (T1 TRM) in ~30% of asthma patients. These patients tend to have more severe asthma, greater exacerbations and higher use of systemic corticosteroids. However, the reliance on bronchoscopy for samples has limited our ability to study the clinical effects of this pathway over time. Furthermore, our understanding of the effects of T1 inflammation on the airways in asthma and the role of T1 TRM cells in maintaining/driving this phenotype are unknown. This study aims to improve our understanding of asthmatic T1 inflammation in three ways: (1) Utilize our T1 dominant murine severe asthma model to assess TRM establishment and reactivation in T1High asthma. (2) To assess the importance of maraviroc (a CCR5 inhibitor) in effecting T1 specific changes on the airway epithelium and mast cell prevalence. (3) The multicenter Severe Asthma Research Program provides clinical data in a large number of asthma subjects with paired sputum samples that will allow us to measure T1 inflammatory markers, assess their correlation with clinical outcomes and identify future biomarkers to better identify T1High asthmatics for future trials. This project will provide unique insight into a novel and poorly understood pathway in asthma with the potential to yield exciting new treatment options for a highly prevalent and severe disease. This study will also provide the opportunity for me to acquire skills in bioinformatics and large ‘omics dataset analysis that will foster my development as a translational physician scientist in severe asthma in addition to advancing my murine model skillset. The work will be carried out at the University of Pittsburgh in the division of Pulmonary, Allergy and Critical Care which has a strong track record of developing physician scientists and boasts a highly developed infrastructure for translational research. I have also assembled a highly accomplished multi-disciplinary mentorship team that is internationally recognized in asthma research, bioinformatics and machine learning. Project Narrative: Asthma is a highly prevalent disease composed of different clinical and biologic phenotypes with variable responses to therapy. We have previously described the presence of Type 1 inflammation in approximately 30-40% of asthma patients which associates with more severe disease and poor response to therapy. This project seeks to expand our understanding of the of the pathologic mechanisms underlying this phenotype as well as the clinical manifestations over time.
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