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）：该试点项目的目标是确定电压门控 L 型 Ca2+ (CaL) 通道对新生儿肺动脉高压 (PH) 发病机制的贡献。使用已建立的新生仔猪缺氧诱导 PH 模型，体内血流动力学显示，暴露于慢性缺氧 (CH) 21 天的新生仔猪静息肺张力增加。对来自同一 CH 仔猪的离体、灌注肺的研究表明，硝苯地平敏感的 CaL 通道导致血管张力异常，并且在来自小肺动脉的膜片钳血管平滑肌细胞中观察到 CaL 电流密度升高。随后的研究揭示了 CH 仔猪肺血管系统中 CaL 通道的成孔 α1C 亚基的显着上调，这对应于促进 CaL 通道运输的辅助 p2a 亚基表达的增加。有趣的是，在培养的小肺动脉中，血栓素 A2 和内皮素-1（这两种与新生儿 PH 相关的血管收缩物质）诱导了这种相同的 CaL 通道异常模式。最后，降低 21 日龄 CH 仔猪血栓素 A2 利用率的预防性治疗可防止肺血管系统中 CaL 通道的上调，并减轻 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，我们将追求特定的目标，旨在：(a) 确定新生仔猪小肺动脉中 CaL 通道的分子组成，(b) 定义血栓素 A2 和内皮素 1 上调 CH 仔猪小肺动脉 CaL 通道的机制基础，以及 (c) 确定血栓素 A2 和内皮素 1 是否上调体内肺血管系统中的 CaL 通道，有助于 PH 的发展。这些研究将提供关于新生儿 PH 期间促进异常 CaL、肺血管系统通道表达的刺激和机制的第一批详细信息，并将有助于确定缓解婴儿和幼儿 PH 的治疗靶点。