has received an $11 million Program Project Grant (PPG) from the National Institutes of Health to define the mechanisms that cause changes in the alveolar epithelium during lung injury.
Jacob I. Sznajder, M.D., Dr. Roy Patterson Professor of Medicine and chief of pulmonary and critical care medicine at the Feinberg School of Medicine, is the principal investigator and head of one of the five research projects and an administrative and a cell culture and physiology core that make up the PPG.
The alveolar epithelium is a layer of plate-like cells that line the air sacs in the lung where oxygen and carbon dioxide are exchanged between alveolar air and pulmonary capillary blood. The layer formed by alveolar epithelial cells is the most resistant component of the alveolo-capillary — or “gas-blood“ — barrier, allowing us to breathe normally and protecting the body from literally drowning in its own fluids.
In lung injury, increased permeability of this barrier and leaks in protein-rich fluid from the capillaries into the alveoli reduce the lung’s ability to pump fluid out of airspaces, causing the patient to “drown from within.”
Normal epithelial function is required for reabsorption of edema fluid and healing of the lungs in patients with acute lung injury and acute respiratory distress syndrome, such as during severe pneumonia, congestive heart failure and SARS. As such, restoration of the alveolar epithelial cell barrier is crucial for recovery from lung injury and normal breathing, Sznajder said.
The Program Project consists a multidisciplinary group of researchers who designed experiments to develop new strategies to expand understanding of the mechanisms mediating epithelial lung injury, particularly the mechanisms by which cells sense and respond to injurious stimuli, such as hypoxia (lack of oxygen), shear, stretch and hyperoxia (abnormally high oxygen level).
The first four projects will determine the mechanisms by which alveolar cells sense stimuli, elucidate signal transduction pathways elicited by these sensors and examine the consequences of the stimuli on epithelial cell sodium pump function, cell cytoskeleton and cell function and survival. The fifth project will examine the mechanisms by which stretch improves non-viral gene transfer to the lung. The projects will promote development of novel tools to investigate the downstream effects of these stimuli on the structure, function and survival of alveolar epithelial cells.
Sznajder is an established investigator in epithelial sodium transport and treatment of patients with respiratory failure due to pulmonary edema. He will lead the first project, which focuses on the effects of severe hypoxia on sodium-potassium ATPpase regulation in the alveolar epithelium.
The second program, led by Robert D. Goldman, Stephen Walter Ransom Professor and chair of cell and molecular biology, and third project, led by Jonathan Jones, professor of cell and molecular biology, will explore the role of the cell cytoskeleton and the extracellular matrix in the pathophysiology of epithelial cell injury.
Navdeep Chandel, assistant professor of medicine and expert in oxygen-sensing and cell apoptosis, will head the fourth project, which will examine the mechanisms regulating alveolar epithelial cell death following exposure to hyperoxia.
The fifth project, led by David Dean, associate professor of medicine and microbiology-immunology, will focus on the mechanisms by which non-viral genes delivered to the alveolar cells via electroporation are transported from the cytoplasm to the nucleus in stretch and non-stretch conditions.
The cell culture and physiology core is led by Karen Ridge, research assistant professor of medicine, and Peter Sporn, associate professor of medicine, and contributes to the Program Project by providing the investigators with the very difficult-to-isolate alveolar epithelial cells and conducting the physiologic studies.
Working on the PPG as co-investigators are Scott Budinger, assistant professor of medicine; Laura Dada, research assistant professor of medicine; David Kamp, associate professor of medicine; and Aaron Ciechanover, visiting professor of medicine and cell and molecular biology and the year 2000 recipient of the Albert and Mary Lasker Award for Basic Medical Research.
Additionally, based on both the caliber of research and the outstanding multidisciplinary group of scientists working on the PPG, the division of pulmonary and critical care medicine has received a five-year training grant for six predoctoral and postdoctoral Ph.D. and M.D. fellowships per year.
NIH-sponsored training grants are awarded only to the nation’s leading research programs.
The grant will enable the program to build on the strengths of current training initiatives in the basic sciences, in translational, public health and health services research and on the considerable scientific and research training experiences of the faculty.