Mentoring Research in Precision Medicine for Lung Disease

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PROJECT SUMMARY By combining a firm understanding of the design and conduct of rigorous human studies with the growing toolkit of the molecular biologist and geneticist, modern patient-oriented physician-scientists have the potential to overcome age-old barriers to the development of targeted therapies in common and morbid respiratory diseases. Accordingly, the first goal of this K24 Mentoring grant renewal application is to continue to protect my time for mentoring of young research scientists in patient oriented translational research in asthma and COPD. This work is a natural extension of work undertaken in the first funding period and builds on the success of my mentees and in further increases in NIH grant support of my research programs. These mentoring efforts have been strongly supported by UCSF through the provision of space to start and expand a “Pulmonary Precision Medicine Core Laboratory” that I direct and which provides scalable space and resources and a common area for didactics and informal research interactions for mentees in patient oriented research (POR). This K24 grant has significantly protected my time and provided resources (some matched by Divisional resources) to ensure the success of this endeavor. In a new direction that I have recently been inspired to pursue, the second goal of this K24 renewal is to support my mentoring efforts in the study of racial disparities in how we assess and treat obstructive lung disease. This new research area flows directly from new data that I and two mentees generated in SPIROMICS, the longitudinal cohort that I direct. These data highlight systematic bias that results from race-adjusted pulmonary function testing equations that are used in research and clinical care. In its structure, this K24 renewal application proposes three scientific aims and a fourth organizational aim which describes my approach to expanding the core training laboratory and seminar series that I have developed by leveraging larger new space that is being conferred to me by the Pulmonary Division and Department of Medicine at UCSF based on the success of these programs to date. Aim 1 will test the hypothesis that airway epithelial endoplasmic reticulum stress identifies a common pathway related to both T2 and interferon-driven inflammation and which is associated with increased disease severity and exacerbation risk in asthma and COPD. Aim 2 will test the hypothesis that maintenance of cilia and detoxifying pathways in the airway epithelium of smokers is associated with clinical resilience in smokers. Aim 3 will test the hypothesis that our current practices for lung function normalization are fundamentally biased and that race-agnostic PFT equations better measure health and disease in our diverse society. Aim 4 will test the hypothesis that the “Pulmonary Precision Medicine Core Laboratory” that I have developed will enhance multidisciplinary training across a range of trainees with diverse scientific backgrounds and enable them to expand their capabilities well beyond their existing core training, while focusing on human studies and POR.