Molecular regulation of pulmonary vascular KCa Channels

描述(申请人提供)：出生时，肺血管扩张伴随着O2张力、通气量和剪切力的增加。当肺动脉(PA)压力不降低时，新生儿持续性肺动脉高压(PPHN)就会发生。PPHN的特点是肺血管张力和反应性增加，严重的中枢性低氧血症，以及对补充02的不完全反应。虽然围产期肺血管扩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钾(KCA)通道的激活。对几个O2传感系统的分子机制的深入研究表明，对O2利用率降低的普遍反应涉及低氧诱导因子1(HIF-1)的表达和活性，HIF-1是参与O2输送或代谢适应低氧的基因的转录激活因子。至少有两个KCA通道亚单位基因具有可能的HIF-1反应元件。综上所述，我们建议检验正常胎儿低氧压环境通过HIF-1介导的转录调控增加肺血管KCA通道表达的工作假说。目的1.低氧调节围产期肺循环中KCA通道亚单位的表达；以及2.低氧通过低氧诱导因子1调节KCA通道基因的表达。识别围产期肺循环中KCA通道表达的机制可能为PPHN的新治疗方法提供特异性的分子靶点。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.