Molecular regulation of pulmonary vascular KCa Channels

描述（由申请人提供）： 出生时，肺血管舒张与O2张力、通气量和剪切应力的增加相关。当肺动脉（PA）压力不降低时，新生儿持续性肺动脉高压（PPHN）的结果。PPHN的特征在于增加的肺血管张力和反应性、严重的中枢性低氧血症和对补充O2的不完全反应。虽然对围产期肺血管舒张的机制还不完全清楚，但最近的数据表明，出生后肺循环的适应取决于钙敏感性K+（KCa）通道的激活。对几种O2传感系统的分子机制的洞察已经证明，对降低的O2可用性的普遍响应涉及缺氧诱导因子1（HIF-1）的表达和活性，HIF-1是参与O2递送或对缺氧的代谢适应的基因的转录激活因子。至少有两个KCa通道亚基基因具有推定的HIF-1反应元件。将这些观察结果结合起来，我们建议测试工作假设，即正常胎儿的低氧张力环境通过HIF-1介导的转录调节增加肺血管KCa通道表达。具体目标是检验以下假设：目标1。缺氧调节KCa通道亚单位在围产期肺循环中的表达;目的2.低氧通过低氧诱导因子1调节KCa通道基因表达鉴定KCa通道在围产期肺循环中表达的机制可能为PPHN的新治疗方法提供特定的分子靶点，PPHN是新生儿发病率和死亡率的持续原因。

DESCRIPTION (provided by applicant): At birth, pulmonary vasodilatation occurs in association with an increase in 02 tension, ventilation, and shear stress. When pulmonary artery (PA) pressure does not decrease, persistent pulmonary hypertension of the newborn (PPHN) results. PPHN is characterized by increased pulmonary vascular tone and reactivity, severe central hypoxemia, and an incomplete response to supplemental 02. While the mechanisms responsible for perinatal pulmonary vasodilatation are incompletely understood, recent data indicate that postnatal adaptation of the pulmonary circulation is contingent upon calcium-sensitive K+ (KCa) channel activation. Insight into the molecular mechanism of several 02 sensing systems has demonstrated that a universal response to reduced 02 availability involves the expression and activity of Hypoxia-lnducible Factor 1(HIF-1), a transcriptional activator of genes involved in 02 delivery or metabolic adaptation to hypoxia. At least two KCa channel subunit genes possess putative HIF-1 response elements. Taking these observations together, we propose to test the working hypothesis that the low oxygen tension environment of the normal fetus increases pulmonary vascular KCa channel expression, through HIF-1 mediated transcriptional regulation. The specific aims are to test the following hypotheses: Aim 1. Hypoxia modulates KCa channel subunit expression in the perinatal pulmonary circulation; and Aim 2. Hypoxia modulates KCa channel gene expression through Hypoxia-lnducible Factor 1. Identification of the mechanisms responsible for KCa channel expression in the perinatal pulmonary circulation may provide a specific molecular target for novel therapeutic approaches to PPHN, an ongoing cause of neonatal morbidity and mortality.