Molecular regulation of pulmonary vascular KCa Channels

肺血管 KCa 通道的分子调控

• 批准号: 6773818
• 负责人: DAVID N. CORNFIELD
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6773818
• 关键词: calcium; congenital cardiovascular disorder; gene expression; genetic transcription; hypoxia inducible factor 1; immunoprecipitation; lung; oxygen tension; polymerase chain reaction; potassium channel; pulmonary hypertension; respiratory hypoxia; shear stress; sheep; tissue /cell culture; western blottings

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.

描述（由申请人提供）：出生时，肺血管扩张与02张力、通气和剪切应力的增加有关。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的特点是肺血管张力和反应性增高，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尚不完全清楚，但最近的数据表明，出生后肺循环的适应取决于钙敏感的K+ (KCa)通道的激活。对几种02传感系统的分子机制的深入研究表明，对02可用性降低的普遍反应涉及缺氧诱导因子1（HIF-1）的表达和活性，HIF-1是一种转录激活因子，参与02的递送或对缺氧的代谢适应。至少有两个KCa通道亚基基因具有假定的HIF-1应答元件。综合这些观察结果，我们提出验证正常胎儿低氧张力环境通过HIF-1介导的转录调控增加肺血管KCa通道表达的工作假设。具体目的是检验以下假设：目标1。缺氧对围产儿肺循环中KCa通道亚基表达的调控和Aim 2。缺氧通过缺氧诱导因子1调控KCa通道基因表达。确定围产期肺循环中KCa通道表达的机制可能为PPHN的新治疗方法提供特定的分子靶点，PPHN是新生儿发病率和死亡率的持续原因。