This is a renewal application for a Specialized Center of Research (SCOR) for Lung Biology and Disease in Infants and Children. The proposal is comprised of a series of fundamental studies aimed at understanding the cellular and molecular aspects of lung injury, growth and development, and these are then coupled with direct clinical studies developing and optimizing therapies for related respiratory disorders in infants. a strong emphasis is placed on pulmonary surfactant-related phenomena in the proposed research, but major effort is also aimed at analyzing and describing a range of cellular, biochemical, and physiological phenomena important in lung disease, injury and development. These objectives are addressed in this SCOR proposal through the following complementary studies: 1) cell and molecular biological studies of growth factors and cytokines from macrophages and other cells, and their effects on type II cells and fibroblasts in normal and injured lungs; 2) molecular biological studies involving specific molecules (TIMP, metallothionein, etc.) whose gene expression and production is altered in lung injury from hyperoxia, fatty acid administration, and other causes, and the regulation and roles of these materials in the injury process; 3) physicochemical studies of the surface activity, component interactions, and biophysical inhibition of natural and synthetic lung surfactants, and the ramifications of these phenomena for the pathophysiology and therapy of lung disease and injury; 4) mechanistic studies of the cell biology, biochemistry, and physiology of acute lung injury in animal models (hyperoxia, barotrauma and surfactant- deficiency, or oleic acid and meconium administration) and how these conditions can be treated with exogenous surfactants, anti-oxidant enzymes, and steroid hormones; and 5) a series of clinical studies involving surfactant replacement and other therapies including jet ventilation for the neonatal Respiratory Distress Syndrome and for neonatal lung injury secondary to pneumonia and meconium aspiration. These inter-related basic science and clinical studies continue and extend our current SCOR research, and are carried out by a multi-disciplinary group of investigators with a history of productive scientific collaboration.
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