Developmental Regulation of O2 Sensing in the Lung

肺中 O2 感应的发育调节

• 批准号: 7038825
• 负责人: DAVID N. CORNFIELD
• 金额: $ 35.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038825
• 关键词: biological signal transduction; calcium flux; congenital cardiovascular disorder; membrane potentials; molecular site; oxygen tension; perinatal; potassium channel; potentiometry; protein structure function; pulmonary artery; pulmonary hypertension; receptor expression; ryanodine; sheep; vascular smooth muscle; vasodilation

DESCRIPTION (provided by applicant): At birth, pulmonary vasodilation occurs in association with an increase in oxygen tension. 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, and an incomplete response to perinatal vasodilator stimuli, including oxygen. Data from our laboratory have demonstrated that the pulmonary circulation responds to an acute increase in oxygen tension via calcium-sensitive K+ channel (BKCa) activation mediated by Ca2+ release from a developmentally regulated ryanodine-sensitive store. Despite the critical importance of oxygen in mediating perinatal pulmonary vasodilation, how oxygen sensing is compromised in PPHN remains unknown. Preliminary data indicate that in an ovine model of PPHN, pulmonary artery smooth muscle cell (PA SMC) BKCa channel expression, oxygen sensing and intracellular cellular Ca2+ homeostasis are compromised. The present proposal tests the working hypothesis that in an animal model of PPHN, pulmonary artery smooth muscle cell oxygen sensing is compromised, thereby attenuating perinatal pulmonary vasodilation. The specific aims are to test the hypotheses that in an ovine model of perinatal pulmonary hypertension: Aim 1. O2 sensing is compromised through both direct and indirect effects on BKCa channel activation; and Aim 2. BKCa channel subunit expression modulates PA SMC O2 sensing. The studies proposed in the present application will determine whether the attenuated response of the pulmonary circulation to vasodilator stimuli, the hallmark of PPHN, results from compromised PA SMC BKCa expression and/or function. Completion of the proposed studies may identify specific molecular target for the development of novel K+ channel based strategies to address a profoundly difficult clinical problem. The strategy of modulating BKCa channel subunit expression to enhance pulmonary vasodilation may be more broadly applicable to other vascular diseases.

描述(申请人提供)：出生时，肺血管扩张与氧分压升高有关。当肺动脉(PA)压力不降低时，新生儿持续性肺动脉高压(PPHN)就会发生。PPHN的特点是肺血管张力和反应性增加，对围产期血管扩张剂刺激(包括氧气)反应不完全。我们实验室的数据表明，肺循环通过钙敏感钾通道(BKCa)的激活来对氧分压的急剧增加做出反应，该激活是由发育调节的兰尼定敏感库中的钙离子释放所介导的。尽管氧气在调节围产期肺血管扩张方面非常重要，但PPHN的氧气感觉如何受损仍不清楚。初步数据表明，在PPHN的绵羊模型中，肺动脉平滑肌细胞(PA SMC)BKCa通道的表达、氧感受和细胞内钙稳态受到破坏。目前的建议验证了PPHN动物模型中的工作假设，即在PPHN的动物模型中，肺动脉平滑肌细胞的氧气感觉受损，从而减弱了围产期的肺血管扩张。目的：1.通过对BKCa通道激活的直接和间接影响，使O2感觉受损；以及2.BKCa通道亚单位的表达调节PA SMC O2感觉。本申请中提出的研究将确定PPHN的标志--肺循环对血管扩张刺激的减弱反应是否源于PA SMC BKCa的表达和/或功能受损。这些研究的完成可能会为开发新的基于K+通道的策略确定特定的分子靶点，以解决一个极其困难的临床问题。调节BKCa通道亚单位表达以增强肺血管扩张的策略可能更广泛地适用于其他血管疾病。