Calcium Channels in Neonatal Pulmonary Hypertension

新生儿肺动脉高压的钙通道

基本信息

批准号：
7467299
负责人：
Nancy J Rusch
金额：
$ 39.14万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7467299
关键词：
Agonist Animals Arkansas Blood Vessels Calcium Channel Cell membrane Cessation of life Child Chronic Co-Immunoprecipitations Collaborations Complex Constriction procedure Development Electrophysiology (science)Elevation Employee Strikes Endothelin Endothelin-1 Felis catus Funding Goals Heart failure Human Hypertension Hypoxia In Vitro Infant Laboratories Lead Lung Mediating Medical Messenger RNA Methods Modeling Molecular Molecular Abnormality Morbidity - disease rate Neonatal Nifedipine Pathogenesis Pattern Pharmacotherapy Pilot Projects Production Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Research Personnel Rest Reverse Transcriptase Polymerase Chain Reaction Smooth Muscle Myocytes Stimulus Thromboxane A2 Time Universities Up-Regulation Vascular remodeling Vasoconstrictor Agents Vasodilator Agents Western Blotting Wisconsin arteriole artery occlusion base college day defined contribution density design hemodynamics immunocytochemistry in vivo infancy inhibitor/antagonist mortality neonatal pulmonary hypertension patch clamp prevent programs prophylactic protein expression receptor research study response therapeutic target trafficking voltage

项目摘要

DESCRIPTION (provided by applicant): The goal of this pilot project is to define the contribution of voltage-gated, L-type Ca2+ (CaL) channels to the pathogenesis of pulmonary hypertension (PH) in the neonate. Using a well established model of hypoxia-induced PH in neonatal piglets, in-vivo hemodynamics revealed an increased resting pulmonary tone in neonatal piglets exposed to chronic hypoxia (CH) for 21 days. Studies in isolated, perfused lungs from the same CH piglets demonstrated that nifedipine-sensitive CaL, channels contributed to the anomalous vascular tone, and an elevated density of CaL current was observed in patch-clamped vascular smooth muscle cells from small pulmonary arteries. Subsequent studies revealed a striking upregulation of the pore-forming alpha1C subunit of the CaL channel in the pulmonary vasculature of CH piglets, which corresponded to an increased expression of the ancillary p2a subunit that promotes CaL channel trafficking. Interestingly, this same pattern of CaL channel abnormalities was induced in cultured small pulmonary arteries by thromboxane A2 and endothelin-1, two vasoconstrictor substances implicated in neonatal PH. Finally, prophylactic therapy to lower thromboxane A2 availability in 21-day CH piglets prevented the upregulation of CaL channels in the pulmonary vasculature and mitigated the development of PH. Based on these key findings suggesting that the upregulation of CaL channels by vasoconstrictor substances contributes to neonatal PH, we will pursue specific aims designed to: (a) identify the molecular composition of CaL channels in small pulmonary arteries of neonatal piglets, (b) define the mechanistic basis by which thromboxane A2 and endothelin-1 upregulate CaL channels in small pulmonary arteries of CH piglets, and (c) determine if thromboxane A2 and endothelin-1 upregulate CaL channels in the pulmonary vasculature in vivo to contribute to the development of PH. These studies will provide the first detailed information on the stimuli and mechanisms that promote abnormal CaL, channel expression in the pulmonary vasculature during neonatal PH, and will assist in identifying therapeutic targets to mitigate PH in infants and young children.

描述（由申请人提供）：该试验项目的目的是定义电压门控的L型Ca2+（Cal）通道对新生儿肺动脉高压（pH）的发病机理的贡献。使用良好的病毒性血流动力学中缺氧诱导的pH值的良好模型显示，暴露于慢性缺氧（CH）的新生儿小猪中的静息肺张力增加了21天。对来自相同CH仔猪的孤立，灌注肺的研究表明，硝苯地平敏感的CAL，通道，导致异常血管张力，并且在斑块夹紧的血管平滑肌细胞中观察到升高的Cal电流密度升高，来自小肺动脉。随后的研究表明，在CH Piglet的肺脉管系统中，CAL通道的孔形成α1c亚基的上调显着上调，这与促进CAL通道运输的辅助P2A亚基的表达增加相对应。有趣的是，血栓烷A2和内皮素-1诱导了培养的小肺动脉中的CAL通道异常模式，两种与新生儿pH有关的血管收缩物质。最后，在21天CH仔猪中降低血栓烷A2的预防疗法阻止了肺脉管系统中Cal通道的上调，并减轻了pH的发展。基于这些关键发现表明，血管收缩物质对CAL通道的上调有助于新生儿pH，我们将追求针对以下特定的目标：仔猪和（c）确定血栓烷A2和内皮素1是否会在体内肺脉管系统中上调CAL通道，从而有助于pH的发展。这些研究将提供有关促进异常CAL的刺激和机制，在新生儿pH值期间肺部脉管系统中的通道表达的第一个详细信息，并将有助于鉴定治疗靶标，以减轻婴儿和幼儿的pH值。