Airway epithelial regulation of fibroblast hyaluronan and versican production in asthmatic airway inflammation

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PROJECT SUMMARY / ABSTRACT This project is a NIH Mentored Clinical Scientist Research Career Development Award (K08) application for Dr. Stephen Reeves, an Acting Assistant Professor in the Department of Pediatrics at the University of Washington (UW). Dr. Reeves has completed his clinical training in Pediatric Pulmonary Medicine and has both a clinical and research interest in the treatment of pediatric asthma. Dr. Reeves’ specific research interest is understanding the role played by the airway epithelial cells (AECs) in regulating the production of extra- cellular matrix (ECM) by airway mesenchymal cells and alterations in this process that may predispose to airway inflammation. His long-term career goal is to establish himself as an independently-funded principle investigator studying these mechanisms in human cells using basic science and translational approaches. In order to achieve this goal, Dr. Reeves is requesting the NIH K08 support for additional training and mentorship in the following specific areas: (1) additional training in airway cell biology including cell-cell and cell-matrix interactions; (2) additional training in the methodology of ECM characterization and quantitation; (3) additional training in laboratory techniques related to gene knockdown and gene editing; (4) additional training in proteomic approaches and data analysis; (5) attendance of scientific conferences, career development seminars, and additional classroom-based training relevant to this project; and (6) mentorship in the development of an independent research focus with a goal of transitioning to scientific independence. In the present application, Dr. Reeves proposes studies to further investigate the role that AEC signaling plays in driving HA and VCAN deposition in the ECM by HLF. These studies will focus on following areas: Specific Aim 1) determining if primary asthmatic AECs drive HLFs to produce an ECM enriched in HA and VCAN as compared to AECs from healthy children; Specific Aim 2) determining if a HA- and VCAN-enriched ECM produced by HLFs conditioned by asthmatic AECs increases leukocyte adhesion, migration, and activation, as compared to ECM produced by HLFs co-cultured with healthy AECs; Specific Aim 3) determining if clinical indices of lung function and airway inflammation among AEC donors correlate with HA and VCAN accumulation in ECM, and with enhanced leukocyte adhesion, migration, and activation by ECM produced by co-cultured HLFs. These studies hold promise in furthering our understanding of how AECs may regulate ECM deposition by HLFs that ultimately protect against or predispose to inflammatory changes, which is at the present poorly understood. Furthermore, it is anticipated these studies would provide the publications and preliminary data needed to develop an independent research direction and apply for R01 funding at the end of the career development support.