Pulmonary immaturity and the accompanying lack of surfactant results in hyaline membrane disease, a major factor in morbidity and mortality associated with premature birth. This disorder is related to lack of synthesis and secretion of lamellar bodies from Type II cells. Proposed research will seek to characterize molecular and humoral mechanisms controlling synthesis and release of surfactant from rat Type II cells in culture. The proposal is based on the hypothesis that catecholamine dependent surfactant release is mediated by activation of c-AMP protein kinase and subsequent protein phosphorylation, enhancing synthesis, processing and secretion of lamellar bodies. We will test whether the dramatic ontogenic appearance of surfactant release prior to birth is related to synthesis of developmentally and humorally regulated cellular components which mediate surfactant synthesis and secretion. Two major areas of work are proposed. The first seeks to associate activation of c-AMP and Ca2+ dependent protein kinases, specific protein phosphorylation (in 32P-phosphate labelled Type II cells) and secretogogue dependent apoprotein and phospholipid secretion from Type II cells. Developmental aspects of the c-AMP surfactant release system will be assessed in fetal Type II epithelial cells. The second area of proposed work will use polyclonal and monoclonal antibodies prepared for surfactant associated apoprotein to characterize synthesis, intracellular processing and secretion of apoprotein (A). Factors controlling the developmental appearance of apoprotein will be determined during late gestation. Molecular characteristics of apoprotein, rates of synthesis and processing (proteolysis, glycosylation and association with phospholipid) will be assessed using pulse-chase techniques after labelling with (35S) methionine, (3H) leucine, (14C) carbohydrates and (3H)choline. Ontogenic regulation of synthesis and processing will be determined in association with phospholipid synthesis and appearance of lamellar bodies. Purification and translation of apoprotein (A) mRNA will be assessed to determine whether developmental appearance of apoprotein (A) production is controlled at transcriptional, translational or post-translational levels. cDNA probes will be prepared to determine gene and protein sequence and to assess regulatory aspects of apo A synthesis.
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