STRUCTURE/FUNCTION ANALYSES OF SPB

Children'S Hospital Med Ctr (Cincinnati), Cincinnati OH

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Abstract

DESCRIPTION (Adapted from the applicant's abstract): Pulmonary surfactant protein B (SP-B) is a 79 amino acid peptide that is associated with surfactant phospholipids in the alveolar space. Mutations in the SP-B gene that result in complete absence of SP-B are fatal in the neonatal period. The pathology associated with SP-B deficiency suggests that SP-B plays a critical role in the synthesis, assembly and metabolism of surfactant. The overall goal of this proposal is to elucidate the role of SP-B in surfactant homeostasis by characterizing the pathophysiology associated with cell-specific expression of SP-B constructs in vivo. Human SP-B constructs, under control of lung cell- specific promoters, will be expressed in SP-B knockout mice to achieve expression of the human transgene in a null background. The effect of transgene expression on lung structure and function will be assessed by biochemical, morphological, and physiological analyses of the surfactant system in fetal and neonatal offspring. The specific aims of this study are to use these mice to study: 1) the functional consequences of over- and underexpression of SP-B; 2) the function of SP-B in Type II and Clara cells; 3) the function of the propeptide domains of the SP-B proprotein; and, 3) the role of inter- and intra-disulfide linkages in SP-B function. These studies will allow characterization of the function of SP-B in the context of the whole animal, define its role in surfactant homeostasis, and facilitate the design of an appropriate therapy for SP-B deficiency.