April 27, 2004
$11 Million Grant Funds Lung Injury Research
CHICAGO --- Northwestern University 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 Ranson
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. |