Pharmacologic Contributors to Patent Ductus Arteriosus

动脉导管未闭的药理学贡献者

• 批准号: 10444540
• 负责人: John Jeffrey Reese
• 金额: $ 72.01万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444540
• 关键词: Adverse effects; Affect; Aminoglycosides; Anemia; Animals; Antacids; Antibiotics; Aorta; Area; Biological Assay; Birth; Blood Vessels; Chronic; Chronic lung disease; Complex; Critical Illness; Cyclooxygenase Inhibitors; Data; Databases; Development; Disease; Diuretics; Drug Combinations; Drug Exposure; Drug Screening; Drug toxicity; Drug usage; Ductus Arteriosus; Evaluation; Exposure to; Failure; Furosemide; Gentamicins; Grant; Human; Hypoxia; Impairment; In Vitro; Kidney; Knowledge; Life; Ligation; Liquid substance; Mediating; Molecular; Morbidity - disease rate; Mus; Muscle Contraction; Myography; Neonatal; Neonatal Intensive Care Units; Newborn Animals; Newborn Infant; Operative Surgical Procedures; Patent Ductus Arteriosus; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacopoeias; Phase; Physiological; Pregnancy; Premature Infant; Property; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Pulmonary artery structure; Relaxation; Research; Risk; Risk Factors; Sepsis; Series; Shunt Device; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Testing; Therapeutic; Time; Toxic effect; Transfusion; Uterus; Vasoconstrictor Agents; Vasodilator Agents; Woman; base; clinically relevant; constriction; cytotoxicity; drug candidate; fetal; fetal blood; gene network; high risk infant; high throughput screening; human data; human tissue; in vivo; innovation; interest; modifiable risk; mortality; mouse model; neonatal human; neonatal mice; neonate; novel; postnatal; premature; prenatal exposure; pressure; preterm newborn; prevent; screening; seal; skills; translational potential

Project Summary Vascular adaptation after birth is dependent on closure of the ductus arteriosus (DA), a fetal vascular shunt connecting the pulmonary artery and aorta. Failure of DA closure results in persistent patency of the DA (PDA), a common disorder associated with increased morbidity and mortality in the most vulnerable infants. Current pharmacological treatments for PDA are limited and only focus on a single therapeutic pathway – cyclooxygenase-mediated prostaglandin (PG) synthesis. However, recent data reveal complex networks of genes and druggable pathways involved in the vasodilatory-to-vasoconstrictive shift that drives postnatal DA closure. Efforts to identify new DA-selective vasoconstrictors overlook the possibility that ongoing vasodilatory stimuli perpetuate DA relaxation and inhibit its closure. Because critically ill preterm newborns are exposed to multiple medications during the time that DA closure takes place, we postulate that pharmacologic agents used in the neonatal ICU prevent DA closure and contribute to PDA. The DA of prematurely-born infants is developmentally primed to respond to vasodilatory signals. Our prior studies using mouse models and human data show that drugs frequently used in preterm infants have unexpected vasodilatory effects on the DA, including specific antibiotics, antacids, and diuretics. These data suggest that drug-induced DA relaxation is a modifiable contributor to PDA, but this has not been systematically evaluated. We therefore hypothesize that drugs commonly used in the NICU have an adverse effect on closure of the premature DA and that specific drug combinations act synergistically to impair postnatal DA closure. Mouse and human tissues will be used to test this hypothesis in three Aims: 1) Determine whether drugs in the neonatal pharmacopeia prevent the initial phase of DA closure - smooth muscle constriction - that leads to physiologic closure of the DA lumen; 2) Determine whether drugs in the neonatal pharmacopeia impair the second phase of DA closure - fibromuscular remodeling - that leads to permanent sealing of the constricted DA; 3) Identify drug combinations that interact to adversely affect either phase of DA closure. Drug effects will be examined using primary (in vitro) high throughput screening (HTS) of preterm mouse DA smooth muscle cells. A series of secondary screening assays will prioritize single- and synergistic combinations of hits based on potency/efficacy, DA-selectivity, and toxicity for further study of their ex vivo and in vivo vasoactive effects on the DA. A novel ex vivo mouse DA-reopening assay will be used to screen for drugs of interest. The effect of hit DA-vasodilatory compounds will be examined on ex vivo human neonatal DA segments and in a large national database of preterm infants. These studies have high translational potential and will definitively identify which drugs or drug combinations pose increased risks for PDA in preterm infants, providing an innovative approach to enhance conservative PDA management efforts in the NICU.

项目摘要 出生后的血管适应依赖于动脉导管(DA)的关闭，DA是一种胎儿血管分流 连接着肺动脉和大动脉。DA关闭失败导致DA(PDA)持续通畅， 这是一种常见的疾病，与最脆弱婴儿的发病率和死亡率增加有关。当前 PDA的药物治疗是有限的，只集中在单一的治疗途径上- 环氧合酶介导的前列腺素(PG)合成。然而，最近的数据揭示了复杂的 参与驱动出生后DA的血管舒缩转变的基因和可用药途径 结案了。寻找新的DA选择性血管收缩药的努力忽略了正在进行的血管扩张 刺激使DA松弛永久化，并抑制其关闭。因为危重的早产儿暴露在 在DA关闭的过程中，我们假设使用了多种药物 在新生儿ICU中，防止DA关闭，有助于PDA的发生。 早产儿的多巴胺在发育过程中准备好对血管扩张信号做出反应。我们的前辈 使用老鼠模型和人类数据的研究表明，经常用于早产儿的药物有 对DA产生意想不到的血管扩张作用，包括特定的抗生素、抗酸剂和利尿剂。这些数据 提示药物诱导的DA松弛是PDA的一个可改变的因素，但这还没有得到系统的研究 已评估。因此，我们假设NICU中常用的药物对 早产DA的关闭和特定的药物组合协同作用损害出生后 DA结案了。老鼠和人体组织将被用来检验这一假说的三个目的：1)确定 新生儿药典中的药物预防DA闭合的初始阶段--平滑肌收缩-- 导致DA管腔的生理性闭合；2)确定新生儿药典中的药物是否损害 DA闭合的第二阶段--纤维肌肉重塑--导致狭窄处的永久性闭合 DA；3)确定相互作用对DA关闭的任一阶段产生不利影响的药物组合。药物效应将会 用原代(体外)高通量筛选(HTS)方法检测早产小鼠DA平滑肌 细胞。一系列二次筛查分析将优先考虑基于单一和协同组合的HITS 为进一步研究它们的体内外血管活性作用，对其效力/效力、DA选择性和毒性进行了研究 地方检察官。一种新的体外小鼠DA重启试验将用于筛选感兴趣的药物。HIT的效果 大血管扩张化合物将在体外的人类新生儿DA节段和大型国家 早产儿数据库。这些研究具有很高的翻译潜力，并将最终确定哪些 药物或药物组合增加了早产儿PDA的风险，提供了一种创新的方法 加强NICU保守的掌上电脑管理工作。