Description of Research Expertise

Research interests

-Intracellular trafficking of protein and lipids
-Receptor-ligand interactions
-Regulation of pulmonary cholesterol and phospholipid metabolism

Particular areas of interest: Surfactant protein A and regulation of surfactant turnover; lung phospholipid clearance and secretion; P63 (CKAP4) as the receptor for surfactant protein A on type II pneumocytes; cholesterol metabolism in the lung; activity of ATP-binding cassette A1 (ABCA1) in alveolar epithelial cells; role of Niemann-Pick C in the regulation of cholesterol homeostasis in type II cells and surfactant.

Research description

Pulmonary surfactant lines the surface of lung alveoli and functions to lower the surface tension at the air-liquid interface, thus preventing end-expiratory collapse. It is composed of a mixture of phospholipid, cholesterol and proteins. My laboratory studies the processes which serve to maintain appropriate surfactant levels under normal conditions and to identify alterations due to disease. Alveolar type II cells produce surfactant, store it in secretory vesicles called lamellar bodies, and release it into the alveolar space. We focus on the regulation of surfactant secretion and uptake by surfactant protein A (SP-A), the most abundant protein in pulmonary surfactant. The importance of SP-A in lung surfactant clearance was demonstrated through use of the SP-A gene-targeted mouse. Using primary cultures of type II pneumocytes we identified P63 (CKAP4) as an SP-A receptor. Regulation of the expression of P63 on the cell surface and interaction of SP-A with P63 was found to be crucial for SP-A-mediation of surfactant turnover. The PI3-kinase signaling pathway played a role in the intracellular transport of P63. Our current focus is identifying the site on the P63 protein that binds to SP-A. The control of these processes will contribute to surfactant homeostasis.

The regulation of lung cholesterol turnover is our second area of research interest. Cholesterol has a major structural and functional role in pneumocytes and surfactant. Pulmonary abnormalities were found due to ATP binding cassette transporter A1 (ABCA1) deficiency in mice and were further characterized by our laboratory. We found ABCA1-mediated the release of cholesterol to apolipoprotein A-1 from both type I and type II alveolar epithelial cells. Our results indicated that the activity of ABCA1 was important for the maintenance of normal lung lipid composition and function. Our attention is currently directed toward exploring the role for Niemann-Pick C (NPC)in cholesterol trafficking in the lung and in the devolopment of alveolar proteinosis seen in NPC patients.