The Research: Pulmonary surfactant is a complex mixture of phospholipids and hydrophobic proteins which maintains alveolar patency. Deficiency of surfactant is the central feature of the fetal respiratory distress syndrome (RDS), a leading cause of mortality in the preterm infant. Males are especially prone to develop RDS (3:1 M:F ratio). In addition, recent studies also implicate a functional deficiency of surfactant with a variety of other acute and chronic lung disorders. The rationale for these studies is that understanding how the fetal lung increases surfactant synthesis, at the enzymatic level, might be critical in devising newer therapies for RDS and other surfactant deficient states. The enzyme CTP:cholinephosphate cytidylyltransferase (CT) is critically involved in the biosynthesis of pulmonary surfactant phospholipid. Evidence to date suggests that the function of this enzyme is highly regulated by lipids. This proposal will examine the overall hypothesis that cytidylyltransferase activity is determined by specific activation or inactivation of the enzyme by lipids rather than by regulation of the amount of enzyme mass or mRNA. The candidate will evaluate the mechanisms by which cytidylyltransferase is developmentally (Aim 1) and hormonally (Aim 3) regulated by specific fatty acids. Finally, this proposal will address the role of potential lipid inhibitor, oleoyl-CoA (Aim 4), on cytidylyltransferase function in the fetal lung. The significance of these studies is that understanding the mechanisms by which lipids regulate the activity of this key enzyme might be critical in understanding how the fetal lung increases surfactant phospholipid synthesis.
| Longo, C A; Tyler, D; Mallampalli, R K (1997) Sphingomyelin metabolism is developmentally regulated in rat lung. Am J Respir Cell Mol Biol 16:605-12 |
| Mallampalli, R K; Mathur, S N; Warnock, L J et al. (1996) Betamethasone modulation of sphingomyelin hydrolysis up-regulates CTP:cholinephosphate cytidylyltransferase activity in adult rat lung. Biochem J 318 ( Pt 1):333-41 |
