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: 10247076
• 负责人: Jerod S. Denton
• 金额: $ 56.22万
• 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/10247076
• 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; Structure; 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/antagonist; 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.

项目总结