Pharmacological Validation of Vascular KATP Channels for Modulating Ductus Arteriosus Tone

调节动脉导管张力的血管 KATP 通道的药理学验证

• 批准号: 10437919
• 负责人: Jerod S. Denton
• 金额: $ 52.88万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437919
• 关键词: Acetaminophen; Alprostadil; Aorta; Arteries; Biological Assay; Biology; Birth; Blood; Blood Vessels; Blood flow; Cantu syndrome; Cardiovascular system; Catheters; Chemicals; Clinical; Closure by clamp; Collaborations; Congenital Heart Defects; Data; Defect; Development; Drug Kinetics; Drug Targeting; Duct (organ) structure; Ductus Arteriosus; Electrophysiology (science); Exhibits; Failure; Fluorescence; Gases; Genetic; Goals; Human; Ibuprofen; In Vitro; Indomethacin; Infant; Institutes; Lead; Left; Libraries; Life; Ligands; Ligation; Link; Lung; Mechanics; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Myography; Neonatal; Neurologic; Newborn Infant; Operative Surgical Procedures; Organ; Patent Ductus Arteriosus; Pathway interactions; Patients; Perfusion; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Physiology; Placental Circulation; Play; Potassium; Potassium Channel; Preparation; Property; Prostaglandins; Pulmonary artery structure; Regulation; Reporting; Risk; Rodent; Role; Savings; Series; Shunt Device; Side; Smooth Muscle Myocytes; Technology; Thallium; Theft; Therapeutic; Time; Validation; analog; base; constriction; drug discovery; efficacy evaluation; experimental study; fetal; gain of function mutation; high throughput screening; in utero; in vivo; inhibitor; lead optimization; mouse model; neonatal mice; new therapeutic target; novel; patch clamp; pup; response; small molecule; small molecule libraries; therapeutic target; tool; vascular bed; vasoconstriction

PROJECT SUMMARY The ductus arteriosus (DA) is an essential fetal artery connecting the aorta and pulmonary artery, which shunts blood away from the developing lungs in utero . Circulatory adaptation at birth requires rapid constriction of the DA to facilitate proper perfusion of the newly inflated lungs. Persistent patency of the neonatal DA (PDA) is a significant clinical problem that is inefficiently managed with currently available therapies. Pharmacology-based PDA therapeutics non-specifically target the prostaglandin pathway, have worrisome off target effects on other vascular beds, and are ineffective in approximately 30% of patients. While surgical ligation and catheter-based closure are effective alternatives, these mechanical approaches come with their own risks and limitations. Consequently, there is a significant need to identify and rigorously validate novel drug targets for manipulating DA tone. An emerging body of physiological and genetic data from our group and others has implicated vascular ATP-regulated potassium (KATP) channels as novel drug targets for regulating DA tone. Specifically, we show here for the first time that KATP channels comprised of pore-forming Kir6.1 and regulatory SUR2B subunits are highly enriched in smooth muscle cells of the PDA and regulate DA tone in response to pharmacological modulation. Unfortunately, the lack of specific Kir6.1/SUR2B inhibitors (and activators) has precluded a rigorous assessment of the therapeutic potential of DA KATP channels for treating PDA. In this multi-PI collaboration, which will benefit from complementary expertise in potassium channel drug discovery (Drs. Denton/Lindsley) and DA physiology and pharmacology (Dr. Shelton), we propose to employ high- throughput screening (HTS) and medicinal chemistry to develop an extensive “tool kit” of vascular-specific KATP channel modulators for validating Kir6.1/SUR2B channels for regulating DA tone in vitro and in vivo. In Aim 1, we will employ a fully validated HTS assay to interrogate ~110,000 small molecules for potent and selective Kir6.1/SUR2B modulators. In Aim 2, we will use medicinal chemistry to optimize lead compounds for selectivity and potency and determine compound metabolism and pharmacokinetic properties. In Aim 3, we will evaluate the efficacy of lead compounds to regulate mouse and human DA tone using isolated vessel myography assays and in vivo mouse models of PDA. The successful completion of these aims will generate critically needed tool compounds for modulating DA tone and validate Kir6.1/SUR2B channels as novel therapeutic targets for treating PDA.

项目摘要 导管（DA）是连接主动脉和肺动脉的必不可少的胎儿动脉 血液远离子宫内发育中的肺部 。 出生时的循环适应需要快速收缩 DA可以促进新膨胀肺的适当灌注。新生儿DA（PDA）的持续通畅是 目前可用的疗法无效地管理的重大临床问题。基于药理学 PDA治疗非特异性靶向前列腺素途径，担心对其他的目标影响 血管床，大约30％的患者无效。而手术连接和基于导管的 关闭是有效的替代方法，这些机械方法具有自身的风险和局限性。 因此，非常需要识别并严格验证新型药物进行操作 da音调。我们小组和其他人的身体和遗传数据的新兴体系已实施 血管ATP调节的钾（KATP）通道是调节DA张力的新型药物靶标。具体来说， 我们首次在这里展示了KATP通道由孔形成Kir6.1和调节性SUR2B组成 亚基高度富集在PDA的平滑肌细胞中，并根据 药理调节。不幸的是，缺乏特定的kir6.1/sur2b抑制剂（和激活剂） 排除了对DA KATP通道治疗PDA的治疗潜力的严格评估。在这个 Multi-Pi合作将受益于钾频道药物发现的完整专业知识 （Denton/Lindsley博士）和DA生理学与药理学（Shelton博士），我们建议员工高级员工 吞吐量筛查（HTS）和医学化学，以开发出广泛的血管特异性KATP的“工具套件” 用于验证KIR6.1/SUR2B通道的通道调节器，用于在体外和体内调节DA音调。在AIM 1中， 我们将采用完全验证的HTS分析来询问〜110,000个小分子，以获得潜力和选择性 KIR6.1/SUR2B调节器。在AIM 2中，我们将使用医学化学来优化铅化合物的选择性 和效力并确定复合代谢和药代动力学特性。在AIM 3中，我们将评估 铅化合物使用孤立的容器myography调节小鼠和人DA音调的效率 PDA的测定和体内小鼠模型。这些目标的成功完成将产生批判性 所需的工具化合物用于调节DA音调并验证Kir6.1/Sur2B通道作为新疗法 治疗PDA的目标。