I have had a longstanding interest and productive history in the field of tissue remodeling, particularly as it relates to lung disease and have been continuously RO1 funded since 1991. I have also had virtually two research lives. For many years my work primarily focused on proteolytic enzymes. My group cloned and characterized several new members of the cathepsin family and elucidated their roles in bone, lung, and immune disorders. I also pursued basic mechanisms by which proteases and adhesion receptors coordinate cell invasion and extracellular matrix remodeling. We were the first to recognize a physical association between proteases (urokinase) and integrins important to migration and invasion. However, after moving to UCSF I have focused my lab on epithelial biology and in particularly pulmonary fibrosis as a disorder of great, unmet medical need and a logical extension of my prior work in matrix biology. I led in vivo investigations of the role of epithelial mesenchymal transition (EMT) in pulmonary fibrosis and in the course of studying epithelial plasticity we discovered a population of lung epithelial progenitors expressing the integrin alpha6/beta4 capable of regenerative activity in vitro and in vivo in response to major injury. Follow-up studies referenced below led to the discovery that the actual stem/progenitor cells are relatively rare distal airway epithelial subpopulations low in mature lineage markers, identifiable in mice by high levels of the Class I antigen H2K-1, and capable of rapid mobilization, proliferation, and pluripotent differentiation in vivo. In humans we have recently identified Type II cells as much more plastic than that of mice, capable of transdiifferentiation and expansion as metaplastic basal cells after major injury. So, in mice airway progenitors mobilize and migrate into alveoli. In humans, alveolar Type II cells transdifferentiate and execute early lung repair locally. This is a surprising finding that is likely to be a major lab focus for the next several years. My lab now is comprised of mainly PhD trainees and research faculty. We are committed to a mechanistic understanding of the cellular basis of alveolar regeneration after lung injury.

I have trained over twenty PhD and/or MD post-docs who now populate academic departments and pharmaceutical labs. As a physician scientist myself, I have particularly enjoyed the responsibility of motivating and training capable young physicians for careers in disease-oriented research. These now include Division and Department Chairs as well as several independent medicine faculty with successful NIH-funded research programs.