Harold A. Chapman, M.D.
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
University of California San Francisco
513 Parnassus Ave.
Box 0111, Rm. HSE-201
San Francisco, California 94143
Dr. Chapman received in his M.D. degree from the University of Alabama in 1972. After internal medicine, pulmonary subspecialty, and research training at the University of Utah, he joined the faculty of Harvard Medical School at the Brigham and Women's Hospital in 1986. He was Professor and Pulmonary Division Chief at University of California at at San Francisco from 2000 to 2008. His major academic activities include his research laboratory, various advisory and editorial boards, and direction of the UCSF Pulmonary Division. He sees patients as a pulmonary consultant in Moffitt-Long Hospital.
Many events in cell and organ function depend on proteolytic enzymes, enzymes which mediate irreversible cleavages in proteins and effect marked alterations in their function, e.g. initiation of coagulation, programmed cell death, maturation of receptors, degradation of antigens, and remodeling of the extracellular matrix. The Chapman lab is focused on the role of proteolytic enzymes in primarily two areas of health and disease: (1) antigen presentation by MHC class II molecules, important to immunity and autoimmunity; and (2) extracellular matrix remodeling important to cell migration and tissue repair. The lab has help identify and define the function of several endosomal cysteine proteases and the biological roles of these enzymes continue to be the major focus of the lab. In MHC class II antigen presentation specific and distinct cysteine enzymes cleave antigen and mediate maturation of class II molecules for surface presentation of antigenic peptides to T cells. One goal of the lab is to define all of the endosomal proteases in antigen presenting cells and test the premise that specific inhibition of one or more of these enzymes can favorably modify the immune response to ameliorate MHC class II driven inflammatory processes such as asthma.
Pathobiology of pulmonary fibrosis, emphysema, and lung cancer
Our recent studies indicate that epithelial cells in the alveolar compartment of the lung undergo a mesenchymal transition (EMT) during fibrogenesis in vivo and that this process is critically regulated by cellular interactions with the baseline and provisional extracellular matrices that develop during injury. Similarly, during the development of emphysema there is accelerated epithelial apoptosis. We are currently interested both in dissecting mechanisms for these processes in model systems and in developing clinical biomarkers that could be used in patients to track these processes during disease progression. Two current clinical projects in which a resident with limited time could actively participate are:
- Biomarkers of IPF progression.
We are currently establishing a database of all ILD subjects referred
to the ILD practice that includes DNA, serum/plasma, and RNA collected
on all new subjects. We now need to obtain one year follow-up specimens
on these patients (> 125) and begin to examine an initial set of
biomarkers. A resident taking on this project, and supported by lab
personnel, could use this as a beginning study for subsequent studies
as a clinical fellow examining disease progression and therapeutic
responses in ILD patients.
- Diagnostic Signature of Lung Proteolytic Activity in Emphysema. We have preliminary data examining the proteomic profile of bronchoalveolar lavage (BAL) fluid from mice susceptible to or resistant to emphysema because of targeted deletion of an elastolytic protease, cathepsin S. We also have comparable samples from nonsmokers and smokers and have tentatively identified protein fragments in the BAL that appear to track with protease activity. A resident could undertake biochemical validation of the specificity and sensitivity of a proteomic signature in human BAL fluid and then use a validated marker to examine sera/BAL from early-onset emphysema patients. A validated biomarker for disease progression currently limits all contemplated clinical trials for intervention in COPD.