Susan H. Guttentag,

Description of Research Expertise

Susan Guttentag, MD
I am a phyician-scientist with experience in clinical neonatology, and research interest in newborn lung disease. Lung surfactant plays an important role in managing both premature and term newborns with lung disease. Surfactant is a soapy material made by cells in the small airspaces of the lung, the alveolar type 2 cells, to maintain inflation of airspaces during the breathing cycle. Diseases of surfactant fall into 3 categories: developmental, genetic, and acquired. The immature lungs of premature infants are often not yet able to make sufficient amounts of surfactant, and these infants develop Respiratory Distress Syndrome (RDS) as a result of the developmental deficiency of surfactant. Surfactant protein B, SP-B, is an important component of surfactant. Infants with a genetic defect in the SP-B gene have normal lung development but poor quality surfactant. As a result, they appear to have RDS even though they were not born prematurely. Full term newborns are born with a full complement of surfactant, but diseases like pneumonia can inactivate normal surfactant, resulting in lung disease. My research focuses on the formation of alveolar type 2 cells in the developing and injured lung, especially regarding the development of surfactant components.

We have used a powerful in vitro model of alveolar type 2 cell differentiation to examine the biosynthesis of surfactant components and more recently to understand the development of lamellar bodies—the surfactant storage organelle—in type 2 cells. This model system has allowed us to use protease inhibitors, RNAi, and plasmids to perturb SP-B processing in vitro as type 2 cells develop. We have collaborated extensively locally, nationally, and internationally to assist other investigators in using this model to understand the transcriptional, epigenetic, and proteomic basis of development of the alveolar epithelium.

More recently, we have been investigating Hermansky-Pudlak Syndrome, a rare form of albinism associated with platelet dysfunction and lung fibrosis. Surfactant is stored in lamellar bodies, a lysosome-like subcellular organelle that is affected in HPS, resulting in giant lamellar bodies. It remains unclear how the HPS gene products contribute to the abnormal lamellar bodies and whether this is important to lung fibrosis in HPS patients. We have a mouse model of HPS—the double mutant pale ear/pearl mouse—that recapitulates the development of lung disease in patients with HPS. In addition to examining the basis for abnormal lamellar body development in HPS, we are using this mouse model to understand the pathobiology of lung disease in HPS with an eye toward developing pre-clinical data for novel therapies. Our recent publication has identified two potential biomarkers of progressive lung disease that have an alveolar epithelial origin.

As the former program director for the Neonatal-Perinatal training program at CHOP and a research mentor for fellows in the program, I have a long-standing interest in research education. In addition to building the research infrastructure for fellows in neonatology at CHOP, I have promoted research career development nationally through my continued involvement in the American Thoracic Society and my prior role in the Organization for Neonatal-Perinatal medicine Training Program Directors.

In short, the focus of my research program is 1) to understand alveolar type 2 cell formation in developing lung, 2) to expand our knowledge of alveolar type 2 cell functions, and 3) to examine the contribution of alveolar type 2 cells to pulmonary physiology and pathophysiology, in both neonates and adults. Potential projects in my lab include:

• Regulation of gene/protein expression in differentiating alveolar type 2 cells
• Mechanisms of lamellar body genesis in alveolar type 2 cells
• Mechanisms of lung injury in Hermansky Pudlak syndrome