The objective of the proposed research project is to study the structure-function relationships of lung phospholipid transfer proteins (PLTPs) and the role of these proteins in lung surfactant biogenesis. Due to the unique phospholipid content of lung surfactant, study of lung PLTPs and other phospholipid-regulating proteins (such as Ca2+-dependent phospholipid binding proteins [PLBPs]) is particularly useful not only for elucidating the function of these proteins, but also for unfolding the unsolved surfactant biogenesis process. The applicant's laboratory has recently made significant progress in characterization of three PLTPs and two PLBPs purified from rabbit lungs. Our data show that PLTPs/PLBPs may play an important role in intracellular surfactant phospholipid assembly, delivery and sorting as well as lung maturation. Due to the complexity of investigating three PLTPs and two PLBPs, the applicant proposes a continued study on rabbit lung PLTPs to test the hypothesis that PLTP(s) regulates intracellular surfactant phospholipid distribution. This hypothesis will be tested by the following interrelated sequence of experiments: (1) investigation of the interactions between PLTP and phospholipids or surfactant phospholipids to better understand the effects of membrane components on the structure, catalytic activity, and substrate specificity of the multiple forms of PLTPs; (2) determination of the primary structures of PLTPs to better understand the structure-function relationship and structure homology or diversity of these proteins; (3) study of the developmental and hormonal regulation of PLTP synthesis in relationship to fetal lung development and maturation;(4) study of the synthesis and regulation of PLTPs in isolated rabbit lung alveolar epithelial type II cells to elucidate the relationships between protein synthesis and surfactant metabolism. These studies will certainly provide important information on the function of PLTPs in lung surfactant biogenesis. The results will also shed light on the structure, function and regulation of these proteins. This research will add crucial new information relevant to lung maturation and will provide a better fundamental understanding of infant respiratory distress syndrome, the leading cause of mortality and morbidity in premature neonates.
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