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

基本信息

批准号：
8464205
负责人：
CANDICE D FIKE
金额：
$ 52.55万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464205
关键词：
Address Animal Model Animals Arginine Aspartate Blood Vessels Breathing Bronchopulmonary Dysplasia Cardiac Cardiopulmonary Cessation of life Chronic Citrulline Clinical Clinical Trials Complication Data Development Disease Drug Kinetics Drug or chemical Tissue Distribution Ensure Enzymes Experimental Designs Exposure to Failure Family suidae Generations Goals Heart Diseases Hypoxia Impairment Infant Knowledge Lead Lung Lung diseases Modeling Multienzyme Complexes Neutral Amino Acid Transport Systems Neutral Amino Acids Newborn Animals Newborn Infant Oral Pathogenesis Pathway interactions Plasma Process Production Publishing Pulmonary Circulation Pulmonary Heart Disease Pulmonary Hypertension Recycling Regimen Reporting Safety Signal Pathway Signal Transduction Source Testing Therapeutic Translating Vasodilator Agents argininosuccinate lyase congenital heart disorder design extracellular improved in vivo Model innovation mature animal neonatal pulmonary hypertension novel prevent public health relevance treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective is to improve therapies for chronic progressive pulmonary hypertension (CPPH) in infants suffering from chronic cardiopulmonary disorders associated with persistent and episodic hypoxia. To do this, we developed a model of CPPH in newborn pigs. We have shown that after 3 days of chronic hypoxia, pulmonary hypertension develops and pulmonary vascular production of the vasodilator NO is intact. When hypoxic exposure is extended to 10 days, pulmonary hypertension worsens and is accompanied by reduced pulmonary vascular NO production. It follows that counteracting or restoring impairments in NO signaling could ameliorate CPPH. Our experimental design will test the hypothesis that treatment with oral L-citrulline, a precursor for L-arginine and NO, increases pulmonary vascular NO production and ameliorates the progressive development of chronic hypoxia-induced pulmonary hypertension. The aims of this proposal are to: 1) evaluate the ability of and mechanisms by which L-citrulline increases pulmonary vascular NO production 2) evaluate the efficacy and safety of oral L-citrulline to ameliorate chronic hypoxia-induced pulmonary hypertension. Treatments started on the day of placement in hypoxia and continued throughout 3 or 10 days total hypoxic exposure will determine the ability to prevent pulmonary hypertension. Treatments started at the end of the 3rd day of hypoxia and continued for the subsequent 7 days of hypoxia will evaluate the ability to arrest or reverse the progression of pulmonary hypertension. As part of the first aim, studies will be performed to address current gaps in our knowledge about L-citrulline sources, availability, and processing. This will include studies to determine whether chronic hypoxia reduces plasma (extracellular) or intracellular levels of L- citrulline, diminishes the expression of neutral amino acid (L-citrulline) transporters, alters L-citrulline uptake, and/or impairs the amounts, activities or complexing of the enzymes and co-precursors (aspartate) needed for adequate intracellular generation/recycling of L-citrulline (e.g. diminished interaction of eNOS and the L- citrulline to L-arginine recycling enzymes, argininosuccinate and argininosuccinate lyase). As part of the second aim, we will perform pharmacokinetic studies of oral L-citrulline to optimize the therapeutic regimen. We will determine if optimized L-citrulline therapy improves the parameters of NO signaling that are perturbed with exposure to chronic hypoxia. These studies will provide invaluable information about offsetting and restoring impaired NO signaling pathways that can ultimately be translated into important clinical trials to treat infants with chronic cardiopulmonary conditions and CPPH due in part to hypoxia.

描述（由申请人提供）：我们的长期目标是改善患有慢性心肺疾病的婴儿慢性进行性肺动脉高压（CPPH）的疗法。为此，我们开发了新生猪中CPPH的模型。我们已经表明，经过3天的慢性缺氧，血管扩张剂NO的肺动脉高压发育和肺血管产生是完整的。当低氧暴露延长至10天时，肺动脉高压会恶化，并伴随着肺血管无产生的降低。因此，反对或恢复损伤在没有信号传导的情况下可以改善CPPH。我们的实验设计将检验以下假设：L-精氨酸和NO的口服L-瓜氨酸的治疗增加了肺血管NO产生，并改善了慢性低氧诱导的肺动脉高压的逐步发展。该提案的目的是：1）评估L-硫氨酸增加肺血管无生产的能力和机制2）评估口服L-citrulline改善慢性低氧诱导的肺高血压的疗效和安全性。治疗从缺氧的当天开始，在整个3或10天的总低氧暴露中持续将决定预防肺动脉高压的能力。治疗始于缺氧第三天结束，随后的7天缺氧将持续评估阻碍或扭转肺动脉高压进展的能力。作为第一个目的的一部分，将进行研究，以解决我们有关L-西曲氨酸来源，可用性和处理的当前差距。这将包括研究以确定慢性低氧降低血浆（细胞外）或细胞内L-瓜氨酸的水平，会降低中性氨基酸（L-甲状腺素）转运蛋白的表达，改变L-citrulline的摄取和/或损害量或将L-硫氨酸的细胞内产生/再生酶（例如，eNOS和L- citrulline与L-精氨酸再生氨酸再生酶相互作用减少）所需的酶和副作用（天冬氨酸）（天冬氨酸）。作为第二个目标的一部分，我们将对口服L-西曲霉的药代动力学研究优化治疗方案。我们将确定优化的L-硫氨酸疗法是否改善了暴露于慢性缺氧的无信号传导的参数。这些研究将提供有关抵消和恢复没有信号通路受损的宝贵信息，这些信号通路最终可以转化为重要的临床试验，以治疗患有慢性心肺疾病的婴儿和CPPH，部分原因是缺氧。