REGULATION OF CYTIDYLYLTRANSFERASE IN FETAL RAT LUNG

肺表面活性物质是一种复杂的磷脂混合物 和维持肺泡开放的疏水蛋白质。 缺乏 表面活性物质的释放是胎儿呼吸窘迫的中心特征 呼吸窘迫综合征（RDS）是早产儿死亡的主要原因。 男性特别容易发生RDS（3：1的M：F比例）。 此外，本发明还提供了一种方法， 最近的研究还暗示了表面活性剂的功能缺陷， 各种其他急性和慢性肺部疾病。 的理由 这些研究就是要了解胎儿的肺是如何增长的 表面活性剂的合成，在酶的水平，可能是至关重要的， 为RDS和其他表面活性物质缺乏状态设计新的治疗方法。 酶CTP：胆碱磷酸胞苷酰转移酶（CT）是关键的 参与肺表面活性物质磷脂的生物合成。 迄今为止的证据表明，这种酶的功能是高度 由脂质调节。 本提案将审查总体假设 胞苷酰转移酶活性由特异性激活决定， 或通过脂质使酶失活，而不是通过调节 酶质量或mRNA的量。 候选人将评估 胞苷酰转移酶的发育机制（目的1）， 通过特定的脂肪酸进行代谢调节（目的3）。 最后 该提案将讨论潜在的脂质抑制剂油酰辅酶A的作用 (Aim 4），对胎肺中胞苷酰转移酶功能的影响。 的 这些研究的意义在于， 哪种脂类调节这种关键酶的活性可能是关键 了解胎儿肺如何增加表面活性剂磷脂 合成.

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.