John Fahy, MD

I am a Professor of Medicine in the Division of Pulmonary and Critical Care Medicine and the Department of Medicine at UCSF. I direct a research program in asthma and other airway diseases that is human centered and focused on uncovering disease mechanisms and improving treatment.

MAJOR GOALS: (i) To define abnormalities in airway epithelial cell function that contribute to abnormal type 2 immune responses in asthma; (ii) To explore mechanisms of formation of pathologic mucus gels in the airway so that novel mucolytics can be developed; (iii) To explore the heterogeneity of molecular mechanisms in asthma to improve prospects for treatment approaches that are patient specific.

(i) ABNORMAL TYPE 2 IMMUNE RESPONSES IN HUMAN ASTHMA: The airway epithelium has emerged as an important regulator of innate and adaptive immune responses that result in type 2 allergic airway inflammation. My lab is specifically investigating epithelial mechanisms that contribute to upregulation of Th2 cytokines in the asthmatic airway. Our experimental approaches include gene and protein expression analysis of airway epithelial brushings, biopsies, and secretions, and cell culture studies in airway epithelial cells from human donors. We collaborate with multiple other UCSF labs, including the Locksley, Ansel, and Woodruff labs.

(ii) PATHOLOGIC MUCUS GELS: The formation of pathologic mucus is a feature of multiple lung diseases and has multiple consequences for lung health, including airflow obstruction and infections. My lab is investigating how pathologic mucus gels form. Our experimental approaches include detailed analyses of sputum samples using rheology-, imaging- and biochemistry-based approaches. We use the data from analysis of pathologic mucus to inform strategies for development of novel mucolytics. Important collaborators include Drs Stefan Oscarson and Stephen Carrington at University College Dublin.

(iii) HETEROGENEITY OF MOLECULAR MECHANISMS IN ASTHMA: Many asthmatics do not respond well to currently available treatments and one reason is that current medications assume a one size fits all approach. My lab is applying a variety of targeted and unbiased approaches to investigate disease mechanism in large numbers of asthmatics with a view to improving understanding of the range and frequency of disease mechanisms that underlie asthma. Our experimental approaches include detailed analysis of the differential expression of genes and proteins in airway biospecimens collected from highly characterized patients with asthma and healthy controls. We also simultaneously explore how simpler tests in blood might reveal specific disease mechanisms and serve as biomarkers for personalizing treatment. Our work in this area is done in collaboration with the Woodruff lab at UCSF and with investigators in the NIH Severe Asthma Research Program (SARP).