Mechanisms of Ductus Arteriosus Regulation

动脉导管调节机制

基本信息

批准号：
7156997
负责人：
John Jeffrey Reese
金额：
$ 37.2万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7156997
关键词：
Acute Address Aorta Birth Blood Vessels Cardiopulmonary Cell Communication Cells Chronic lung disease Closure Condition Congenital Disorders Constriction procedure Coxibs Cultured Cells Cyclooxygenase Inhibitors Data Development Disruption Ductus Arteriosus Electron Microscopy Endocrine Exposure to Failure Fetal Development Genetic Human Hyperbaric Oxygenation In Vitro Indomethacin Infant Knock-out Knockout Mice Legal patent Ligands Ligation Lung Measures Mediating Mediator of activation protein Modeling Mus Neonatal Newborn Infant Operative Surgical Procedures Patent Ductus Arteriosus Pathway interactions Pharmaceutical Preparations Phenotype Play Positioning Attribute Pregnancy Premature Infant Premature Labor Process Prostaglandin E Receptor Prostaglandin Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Isoforms Pulmonary artery structure Purpose Receptor Signaling Regulation Relaxation Risk Role Shunt Device Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Source Staging Stimulus Testing Time Tissues Transgenic Organisms Vasoconstrictor Agents Vasodilation Withdrawal Woman clinically significant concept critical developmental period cyclooxygenase 1 cyclooxygenase 2 expectation fetal human WFDC2 protein in utero in vivo novel postnatal prenatal exposure prevent programs prostaglandin EP4 receptor pup receptor research study response stem vascular bed

项目摘要

DESCRIPTION (provided by applicant): Vascular transition at birth is dependent on relaxation of the pulmonary vasculature and constriction of the ductus arteriosus (DA), which occur soon after delivery. The mechanisms that regulate these opposing effects are not fully resolved. Cyclooxygenase (COX)-derived prostaglandins play a critical role in DA regulation. Suppression of prostaglandin synthesis by COX inhibition usually results in constriction of the fetal or neonatal DA. Paradoxically, some women who receive COX inhibitors during pregnancy have infants with persistent patency of the DA (PDA) instead of DA constriction. In addition, mice genetically deficient for both COX isoforms or for the EP4 prostaglandin receptor die soon after birth with a PDA. The mechanisms that render the DA naive to contractile stimuli under these conditions are unknown. Our preliminary data suggests that disruption of prostaglandin actions by genetic deletion or prolonged pharmacologic inhibition results in PDA due to alterations in the normal process that directs maturation and sensitivity of the DA. We hypothesize that prostaglandin signaling directs a developmental program that instills responsiveness of the DA to other vasoactive mediators later in gestation and after birth. To test this possibility, the PDA of COX-1/COX-2 double null mice and mice lacking the EP4 prostaglandin receptor will be examined. Transgenic and pharmacological studies will be used to define the critical stage of development for DA responsiveness. Mice with conditional deletion of EP4 and COX-1/COX-2 will help determine the timing and source of prostaglandin actions in the DA. DA endothelial - smooth muscle interactions will be examined in cell culture and transgenic experiments. Pathways for intracellular prostaglandin actions in DA cells will be defined. Alterations in DA function will be evaluated in vivo and in vitro by examining changes in DA patency or measuring changes in DA tone. We will also identify DA mediators that are potential downstream targets of prostaglandin receptor signaling. Understanding DA regulation is clinically important since premature closure of the DA in utero can result in fetal compromise, while a PDA is one of the most frequent congenital disorders, leading to impaired cardiopulmonary function and placing infants at risk for chronic lung disease. These studies will examine new roles for prostaglandins and their relationship with other vasoactive mediators during development.

描述（由申请人提供）：出生时的血管过渡取决于肺血管的松弛和动脉导管（DA）的收缩，该肺导管（DA）发生在分娩后不久。调节这些相反效应的机制尚未完全解决。环氧合酶（COX）衍生的前列腺素在DA调节中起关键作用。 COX抑制对前列腺素合成的抑制通常会导致胎儿或新生儿DA的收缩。矛盾的是，一些在怀孕期间接受COX抑制剂的女性患有DA（PDA）持续通畅而不是DA收缩的婴儿。此外，小鼠在cox同工型或EP4前列腺素受体中的遗传缺陷在出生后不久就死于PDA。在这些条件下，使DA幼稚刺激的机制尚不清楚。我们的初步数据表明，由于指导DA的正常过程的变化，遗传缺失或长期药理抑制作用会导致PROSTAGLANDIN作用的破坏导致PDA。我们假设前列腺素信号指导了一项发育计划，该计划灌输了DA对其他血管活性介质后期和出生后的反应性。为了测试这种可能性，将检查COX-1/COX-2双null小鼠的PDA和缺乏EP4前列腺素受体的小鼠。转基因和药理学研究将用于定义DA反应性发展的关键阶段。具有条件缺失EP4和COX-1/COX-2的小鼠将有助于确定DA中前列腺素作用的时机和来源。 DA内皮 - 平滑肌相互作用将在细胞培养和转基因实验中进行检查。将定义在DA细胞中细胞内前列腺素作用的途径。 DA功能的改变将在体内和体外评估通过检查DA通畅性的变化或测量DA音调的变化。我们还将确定DA介体是前列腺素受体信号传导的潜在下游靶标。了解DA调节在临床上很重要，因为在子宫内的DA过早关闭可能会导致胎儿妥协，而PDA是最常见的先天性疾病之一，导致心肺功能受损，并使婴儿处于患慢性肺病的风险。这些研究将研究前列腺素的新作用及其在发育过程中与其他血管活性介质的关系。