Developmental Regulation of O2 Sensing in the Lung

肺中 O2 感应的发育调节

基本信息

  • 批准号:
    7637851
  • 负责人:
  • 金额:
    $ 33.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-09-30 至 2013-06-30
  • 项目状态:
    已结题

项目摘要

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(由申请人提供):出生时,肺血管舒张与氧分压增加相关。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的特征是肺血管张力和反应性增加,以及对围产期血管扩张刺激(包括氧气)的不完全反应。来自我们实验室的数据表明,肺循环响应急性增加的氧张力通过钙敏感性K+通道(BKCa)激活介导的钙释放从发育调节ryanodine敏感的商店。尽管氧在介导围产期肺血管舒张中至关重要,但PPHN中氧传感如何受损仍不清楚。初步数据表明,在绵羊PPHN模型中,肺动脉平滑肌细胞(PA SMC)BKCa通道表达,氧敏感和细胞内Ca 2+稳态受到损害。目前的建议测试的工作假设,在动物模型的PPHN,肺动脉平滑肌细胞氧传感受损,从而减弱围产期肺血管舒张。具体的目的是测试的假设,在绵羊模型的围产期肺动脉高压:目的1。通过对BKCa通道激活的直接和间接影响,O2传感受到损害;目的2。BKCa通道亚单位表达调节PA SMC O2感受。本申请中提出的研究将确定肺循环对血管扩张剂刺激的减弱反应(PPHN的标志)是否是由受损的PA SMC BKCa表达和/或功能引起的。完成拟议的研究可能会确定特定的分子靶点,用于开发新的基于K+通道的策略,以解决一个非常困难的临床问题。调节BKCa通道亚单位表达以增强肺血管舒张的策略可能更广泛地适用于其他血管疾病。

项目成果

期刊论文数量(28)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Chronic intrauterine pulmonary hypertension selectively modifies pulmonary artery smooth muscle cell gene expression.
Acute normoxia increases fetal pulmonary artery endothelial cell cytosolic Ca2+ via Ca2+-induced Ca2+ release.
急性常氧通过 Ca2 诱导的 Ca2 释放增加胎儿肺动脉内皮细胞胞质 Ca2。
  • DOI:
    10.1203/01.pdr.0000233077.29866.f0
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    3.6
  • 作者:
    Tirosh,Raz;Resnik,ErnestoR;Herron,Jean;Sukovich,DavidJ;Hong,Zhigang;Weir,EKenneth;Cornfield,DavidN
  • 通讯作者:
    Cornfield,DavidN
Pulmonary vascular response to normoxia and K(Ca) channel activity is developmentally regulated.
Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells.
Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation.
  • DOI:
    10.1161/circresaha.112.300646
  • 发表时间:
    2013-04-26
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    Kim YM;Barnes EA;Alvira CM;Ying L;Reddy S;Cornfield DN
  • 通讯作者:
    Cornfield DN
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DAVID N. CORNFIELD其他文献

DAVID N. CORNFIELD的其他文献

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{{ truncateString('DAVID N. CORNFIELD', 18)}}的其他基金

Stanford Training Program in Lung Biology
斯坦福大学肺生物学培训计划
  • 批准号:
    10089188
  • 财政年份:
    2016
  • 资助金额:
    $ 33.69万
  • 项目类别:
Stanford Training Program in Lung Biology
斯坦福大学肺生物学培训计划
  • 批准号:
    10652968
  • 财政年份:
    2016
  • 资助金额:
    $ 33.69万
  • 项目类别:
Stanford Training Program in Lung Biology
斯坦福大学肺生物学培训计划
  • 批准号:
    9979930
  • 财政年份:
    2016
  • 资助金额:
    $ 33.69万
  • 项目类别:
Stanford Training Program in Lung Biology
斯坦福大学肺生物学培训计划
  • 批准号:
    10379231
  • 财政年份:
    2016
  • 资助金额:
    $ 33.69万
  • 项目类别:
Postnatal Lung Development: Mechanisms of Molecular and Vascular Development
产后肺发育:分子和血管发育机制
  • 批准号:
    7936134
  • 财政年份:
    2009
  • 资助金额:
    $ 33.69万
  • 项目类别:
Postnatal Lung Development: Mechanisms of Molecular and Vascular Development
产后肺发育:分子和血管发育机制
  • 批准号:
    7861290
  • 财政年份:
    2009
  • 资助金额:
    $ 33.69万
  • 项目类别:
Molecular regulation of pulmonary vascular KCa Channels
肺血管 KCa 通道的分子调控
  • 批准号:
    6940632
  • 财政年份:
    2003
  • 资助金额:
    $ 33.69万
  • 项目类别:
Molecular Regulation of Pulmonary Vascular KCa Channel
肺血管 KCa 通道的分子调控
  • 批准号:
    8656382
  • 财政年份:
    2003
  • 资助金额:
    $ 33.69万
  • 项目类别:
Molecular regulation of pulmonary vascular KCa Channels
肺血管 KCa 通道的分子调控
  • 批准号:
    6773818
  • 财政年份:
    2003
  • 资助金额:
    $ 33.69万
  • 项目类别:
Molecular Regulation of Pulmonary Vascular KCa Channel
肺血管 KCa 通道的分子调控
  • 批准号:
    8490606
  • 财政年份:
    2003
  • 资助金额:
    $ 33.69万
  • 项目类别:

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