Prostanoids and hypoxic neonatal pulmonary hypertension
前列腺素与缺氧新生儿肺动脉高压
基本信息
- 批准号:6620319
- 负责人:
- 金额:$ 25.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-12-01 至 2004-11-30
- 项目状态:已结题
- 来源:
- 关键词:RNase protection assay biological signal transduction blood flow measurement disease /disorder etiology disease /disorder model fatty acid metabolism gene expression hemodynamics hypoxia microelectrodes muscle cells newborn animals potassium channel prostacyclins prostaglandin endoperoxide synthase protein localization protein structure function pulmonary artery pulmonary hypertension respiratory oxygenation smooth muscle swine thromboxanes vascular endothelium video microscopy western blottings
项目摘要
The pathophysiology underlying neonatal pulmonary hypertension has received relatively little study compared to adult models, even though it may involve different mechanisms. Thus, the long-term goal is to improve the understanding of the pathogenesis of neonatal pulmonary hypertension so that more effective therapies can be developed. Almost all of the research regarding neonatal pulmonary hypertension has been directed at devising therapies to acutely decrease pulmonary vascular resistance. Therapies for preventing the onset or progression of neonatal pulmonary hypertension have received little attention and have largely involved manipulating the nitric oxide (NO) pathway. Yet, not all infants respond favorably to inhaled NO. Our preliminary data demonstrate that rather than a singular effect attributable to NO, derangements in the prostanoid system, which include prostacyclin (PGI2) and thromboxane (TXA2), are key to the pathogenesis of hypoxia-induced neonatal pulmonary hypertension. Our overall hypothesis is that distinct disruptions of the prostanoid signaling pathway occur with sustained hypoxia in endothelial cells and smooth muscle cells of small pulmonary arteries (SPA) and lead to inappropriate constriction of pulmonary resistance vessels and the development of pulmonary hypertension. At the core of our methodology is the use of SPA as they are the vascular site most relevant to the development of pulmonary hypertension. This proposal will investigate the following specific hypotheses: (a) the cyclooxygenase (COX) 1-PGI2 axis is disrupted in endothelial cells of SPA with sustained hypoxemia leading to decreased dilator prostanoid production; (b) the COX 2-TXA2 axis is enhanced in smooth muscle cells of SPA with sustained hypoxia so that the ratio of constrictor to dilator prostanoid production is increased; (c) the change in ratio of constrictor to dilator prostanoid production alters smooth muscle cell K+ conductance and membrane potential leading to inappropriate constriction and pulmonary hypertension. Specific Aim 1 will (a) determine the amounts, cellular sources and relative contributions of COX 1 and COX 2 biosynthetic pathways to PGI2 and TXA2 production using enzyme immunoassay (EIA) and cannulated artery techniques; (b) evaluate the effect of PGI2 and TXA2 on SPA tone (cannulated artery technique); (c) establish the predominant cellular localization of the major prostanoid enzymes (immunostaining technique) and (d) determine the role of various K+ channels in mediating vascular responses to PGI2 (microelectrode technique). Specific Aim 2 will (a) determine whether the amounts and/or predominant cellular sources of production of PGI2 and TXA2 are altered in SPA from piglets exposed to chronic hypoxia (EIA and cannulated artery techniques); (b) evaluate whether the sensitivity to PGI2 and TXA2 has been altered by chronic hypoxia (cannulated artery technique); (c) determine whether mRNA levels for the major enzymes (RNase protection assay), protein abundance of the major enzymes (immunoblot technique) or the cellular localization of the major enzymes (immunostaining) underlying PGI2 and TXA2 production are affected by chronic hypoxia; (d) evaluate whether the effect from K+ channels in mediating dilation and constriction from PGI2 and TXA2 is involved with the development of pulmonary hypertension (microelectrode technique). These studies should provide important information for improving treatment of infants with pulmonary hypertension.
与成人模型相比,新生儿肺动脉高压的病理生理学研究相对较少,尽管其可能涉及不同的机制。因此,长期目标是提高对新生儿肺动脉高压发病机制的认识,以便开发更有效的治疗方法。 几乎所有关于新生儿肺动脉高压的研究都是针对设计急性降低肺血管阻力的治疗方法。 用于预防新生儿肺动脉高压的发作或进展的疗法很少受到关注,并且主要涉及操纵一氧化氮(NO)途径。 然而,并不是所有的婴儿吸入NO反应良好。我们的初步数据表明,而不是一个单一的效果归因于NO,前列腺素系统,其中包括前列环素(PGI2)和血栓素(TXA2)的紊乱,是缺氧引起的新生儿肺动脉高压的发病机制的关键。 我们的总体假设是,前列腺素信号通路的明显中断发生在小肺动脉(SPA)的内皮细胞和平滑肌细胞中的持续缺氧,并导致肺阻力血管的不适当收缩和肺动脉高压的发展。 我们方法的核心是使用SPA,因为它们是与肺动脉高压发展最相关的血管部位。 本研究拟探讨以下假说:(a)持续低氧时SPA内皮细胞环氧化酶(考克斯)1-PGI2轴被破坏,导致扩张器前列腺素生成减少;(b)持续低氧时SPA平滑肌细胞考克斯2-TXA2轴增强,导致收缩器前列腺素生成与扩张器前列腺素生成的比值增加;(c)收缩肌与扩张肌前列腺素类生成比例的变化改变了平滑肌细胞K+电导和膜电位,导致不适当的收缩和肺动脉高压。 具体目标1将(a)使用酶免疫测定(EIA)和插管动脉技术确定考克斯1和考克斯2生物合成途径对PGI2和TXA2产生的量、细胞来源和相对贡献;(B)评价PGI2和TXA2对SPA张力的影响。(插管动脉技术);(c)确定主要前列腺素酶的主要细胞定位(d)确定各种K+通道在介导血管对PGI2的反应中的作用(微电极技术)。具体目标2将(a)确定在来自暴露于慢性缺氧的仔猪的SPA中,PGI2和TXA2的产生的量和/或主要细胞来源是否改变(EIA和插管动脉技术);(B)评估对PGI2和TXA2的敏感性是否已被慢性缺氧改变(插管动脉技术);(c)确定主要酶的mRNA水平(RNA酶保护测定),主要酶的蛋白质丰度(免疫印迹技术)或主要酶的细胞定位(免疫染色)潜在的PGI_2和TXA_2的产生受慢性缺氧的影响;(d)评估K+通道介导PGI2和TXA2的扩张和收缩的作用是否与肺动脉高压的发展有关(微电极技术)。这些研究将为改善婴儿肺动脉高压的治疗提供重要信息。
项目成果
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CANDICE D FIKE其他文献
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{{ truncateString('CANDICE D FIKE', 18)}}的其他基金
Chronic progressive hypoxia-induced pulmonary hypertension in newborns
新生儿慢性进行性缺氧引起的肺动脉高压
- 批准号:
9195826 - 财政年份:2015
- 资助金额:
$ 25.2万 - 项目类别:
Chronic progressive hypoxia-induced pulmonary hypertension in newborns
新生儿慢性进行性缺氧引起的肺动脉高压
- 批准号:
8259437 - 财政年份:2010
- 资助金额:
$ 25.2万 - 项目类别:
Chronic progressive hypoxia-induced pulmonary hypertension in newborns
新生儿慢性进行性缺氧引起的肺动脉高压
- 批准号:
8063892 - 财政年份:2010
- 资助金额:
$ 25.2万 - 项目类别:
Chronic progressive hypoxia-induced pulmonary hypertension in newborns
新生儿慢性进行性缺氧引起的肺动脉高压
- 批准号:
8464205 - 财政年份:2010
- 资助金额:
$ 25.2万 - 项目类别:
Chronic progressive hypoxia-induced pulmonary hypertension in newborns
新生儿慢性进行性缺氧引起的肺动脉高压
- 批准号:
7916262 - 财政年份:2010
- 资助金额:
$ 25.2万 - 项目类别:
Prostanoids and Hypoxic Neonatal Pulmonary Hypertension
前列腺素与新生儿缺氧性肺动脉高压
- 批准号:
7430433 - 财政年份:2001
- 资助金额:
$ 25.2万 - 项目类别:
Prostanoids and Hypoxic Neonatal Pulmonary Hypertension
前列腺素与新生儿缺氧性肺动脉高压
- 批准号:
7142124 - 财政年份:2001
- 资助金额:
$ 25.2万 - 项目类别:
Prostanoids and Hypoxic Neonatal Pulmonary Hypertension
前列腺素与新生儿缺氧性肺动脉高压
- 批准号:
7256220 - 财政年份:2001
- 资助金额:
$ 25.2万 - 项目类别:
Prostanoids and Hypoxic Neonatal Pulmonary Hypertension
前列腺素与新生儿缺氧性肺动脉高压
- 批准号:
7637859 - 财政年份:2001
- 资助金额:
$ 25.2万 - 项目类别:
Prostanoids and hypoxic neonatal pulmonary hypertension
前列腺素与缺氧新生儿肺动脉高压
- 批准号:
6415638 - 财政年份:2001
- 资助金额:
$ 25.2万 - 项目类别:
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