REGULATION OF CYTIDYLYLTRANSFERASE IN FETAL RAT LUNG

研究：肺表面活性物质是一种复杂的磷脂混合物 以及维持肺泡通畅的疏水蛋白。缺憾 表面活性物质是胎儿呼吸窘迫的主要特征 综合征(RDS)，早产儿死亡的主要原因。 男性尤其容易发生RDS(男女比例为3：1)。此外, 最近的研究还表明，表面活性物质存在功能缺陷 各种其他急性和慢性肺部疾病。其基本原理是 这些研究表明，了解胎儿肺是如何增加的 表面活性剂的合成，在酶的水平上，可能是关键的 为RDS和其他表面活性物质缺乏状态设计新的治疗方法。 CTP酶：磷酸胆碱胞苷转移酶(CT)是至关重要的 参与肺表面活性物质磷脂的生物合成。 到目前为止的证据表明，这种酶的功能是高度 受脂类调节。这项提议将检验总体假设 胞苷酰基转移酶的活性是由特定的激活决定的 或通过脂类而不是通过调节 酶质量或信使核糖核酸的量。候选人将评估 胞苷酰转移酶的发育机制(目标1)和 荷尔蒙(目标3)受特定脂肪酸调节。最后，这一点 提案将涉及潜在的脂类抑制剂油酰辅酶A的作用 (目的4)，对胎肺胞苷转移酶功能的影响。这个 这些研究的意义在于，通过 哪些脂类调节这一关键酶的活性可能是至关重要的 了解胎肺如何增加表面活性物质磷脂 综合。

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.