Hormonal Regulation of Surfactant Protein mRNA Stability

表面活性蛋白是肺表面活性物质的重要功能组分，肺表面活性物质是一种复合脂蛋白，其作用是降低肺泡表面张力。 编码表面活性蛋白SP-A、SP-B、SP-C和SP-D的基因的表达在胎儿肺组织中受到发育调节。 早产儿由于缺乏足够的表面活性剂合成，可发展为呼吸窘迫综合征（RDS）。RDS是发达国家新生儿发病和死亡的主要原因。用糖皮质激素治疗婴儿和孕妇可加速肺成熟，降低RDS的风险。表面活性剂蛋白B（SP-B）是表面活性剂功能的重要组成部分。 缺乏SP-B蛋白的表面活性剂导致足月婴儿呼吸衰竭，而含有降低水平的SP-B蛋白的表面活性剂在降低肺泡表面张力的能力方面无效。糖皮质激素通过转录激活和表面活性蛋白mRNA稳定性改变人胎肺表面活性蛋白表达。 特别是，糖皮质激素增加SP-B mRNA的转录表达和稳定性。 由于糖皮质激素在临床上用于治疗早产儿，因此了解糖皮质激素调节胎肺II型上皮细胞表面活性蛋白基因表达的分子机制非常重要。 本研究的目的是确定糖皮质激素稳定人SP-B mRNA同时使SP-A mRNA不稳定的分子机制。 提出了以下具体目标：（1）功能定位SP-B mRNA中通过糖皮质激素介导调节人SP-B mRNA稳定性的区域;（2）表征在糖皮质激素介导调节人SP-B mRNA稳定性的顺式作用元件处的体外mRNA：蛋白质相互作用;和（3）鉴定介导调节人SP-B mRNA稳定性的蛋白质并研究其调节。本研究的目的是确定胎儿肺发育过程中糖皮质激素通过转录后机制增强SP-B基因表达和减少SP-A基因表达的分子机制，从而为设计治疗方案提供见解，以提高产前糖皮质激素在增强胎儿肺表面活性物质合成和预防RDS方面的有效性。

Surfactant proteins are important functional components of pulmonary surfactant, a complex lipoprotein that acts to reduce lung alveolar surface tension. Expression of the genes encoding surfactant proteins, SP-A, SP-B, SP-C, and SP-D is developmentally regulated in fetal lung tissue. Prematurely born infants can develop Respiratory Distress Syndrome (RDS), due to a lack of adequate surfactant synthesis. RDS is the leading cause of neonatal morbidity and mortality in developed countries. Treatment of infants and pregnant mothers with glucocorticoids accelerates lung maturity, decreasing the risk of RDS. Surfactant protein B (SP-B) is a critical component in the function of surfactant. Surfactant that is deficient in SP-B protein results respiratory failure in full term infants, and surfactant that contains reduced levels of SP-B protein is not effective in the ability to reduce lung alveolar surface tension. Glucocorticoids alter surfactant protein expression in fetal human lung via both transcriptional activation and by altering the stability of surfactant protein mRNA. In particular, glucocorticoids increase both the transcriptional expression and the stability of SP-B mRNA. Since glucocorticoids are used clinically in treatment of premature infants, it is important to understand the molecular mechanism(s) by which glucocorticoids act to regulate surfactant protein gene expression in type II epithelial cells in fetal lung. The objective of the proposed research is to define the molecular mechanism(s) by which glucocorticoids stabilize human SP-B mRNA while destabilizing SP- A mRNA. The following specific aims are proposed: (1) functionally localize the region(s) in the SP-B mRNA that mediates regulation of human SP-B mRNA stability by glucocorticoids in vivo; (2) characterize the in vitro mRNA:protein interactions at the cis-acting element(s) that mediate regulation of human SP-B mRNA stability by glucocorticoids; and (3) identify the protein(s) that mediates regulation of human SP-B mRNA stability and study its regulation. The goal of this research is to define the molecular mechanisms whereby glucocorticoids enhance SP-B gene expression and reduce SP-A gene expression by post-transcriptional mechanisms during fetal lung development and, therefore provide insight into the design of treatment regimens that increase the effectiveness of antenatal glucocorticoids in the enhancement of surfactant synthesis by the fetal lung and prevent RDS.