Discovery of small molecule regulators of atrial cardiomyocyte action potential duration to restore normal cardiac rhythm in atrial fibrillation

发现心房心肌细胞动作电位持续时间的小分子调节剂以恢复心房颤动的正常心律

• 批准号: 10643997
• 负责人: Alexandre Romain Colas
• 金额: $ 48.75万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643997
• 关键词: Action Potentials; Affect; Aging; Animal Model; Anticoagulants; Arrhythmia; Atrial Fibrillation; Attention; Biological; Biological Assay; Biology; Cardiac; Cardiac Myocytes; Cardiac ablation; Cardiovascular Diseases; Cardiovascular system; Catalogs; Cells; Cellular Assay; Cellular biology; Chemicals; Clinical; Critical Pathways; Data; Developing Countries; Disease; Dose; Dryness; Electrophysiology (science); Exclusion; Future; Generations; Genetic; Goals; Grant; Heart Atrium; Heart Diseases; Heart failure; Human; Image; Kinetics; Lead; Mutation; Myocardial; Outcome; Output; Parents; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Physiology; Powder dose form; Procedures; Proliferating; Property; Quality of life; Readiness; Reporting; Research; Resolution; Resources; Safety; Series; Stroke; Structure-Activity Relationship; Symptoms; Systems Analysis; Technology; Testing; Therapeutic; Thromboembolism; Tissues; Toxic effect; Treatment Cost; Validation; Ventricular; Work; analog; cheminformatics; cost; design; drug discovery; electrical property; experimental study; heart function; heart rhythm; high throughput screening; improved; in vivo evaluation; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; innovation; liquid chromatography mass spectrometry; mortality; novel; novel therapeutics; progenitor; response; scaffold; screening; side effect; small molecule; small molecule libraries; statistics; stem cells; stroke risk; tool; trait

PROJECT SUMMARY Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, afflicting over 33 million people worldwide and 6 million in the US. AF causes reduced quality of life, stroke and systemic thromboembolism, heart failure, and increased mortality. Treatment of AF and its complications with nonspecific drugs or procedures is characterized by unsatisfactory outcomes and significant cost. Acquired heart disease, cardiac remodeling, neurohormonal factors, aging, and genetic traits have all been correlated with presence of AF. Rapid, uncoordinated atrial chamber activity is due to shortened or prolonged cardiomyocyte action potential durations acting within a vulnerable myocardial substrate, causing persistent arrhythmia that features triggering or sustaining circuit re- entry or early and/or delayed after-depolarizations, respectively. We have recently developed a novel, high throughput kinetic imaging and analysis platform to characterize cardiomyocyte electrophysiological properties at single cell resolution, which can be used to conduct high throughput screening (HTS) on functional human atrial cardiomyocytes derived from Id1-programmed cardiac progenitors created from iPS cells. Our innovation is the use of this and related assays in a phenotypic screening cascade designed to discover previously unknown, atrial-specific modulators of cardiomyocyte electrical properties and rhythm. Our hypothesis is this approach will ultimately generate drug-like starting points for future disease-modifying cardiovascular therapeutics. The primary HTS assay has been fully optimized in a 384-well format, and as a demonstration of assay readiness, 400 compounds have been screened (Kolmogorov-Smirnov D-statistic >0.1). Multiple hits from pilot screens were identified and were confirmed and validated in concentration response experiments. A battery of downstream assays has been developed and piloted to establish a critical path-testing funnel. Several compounds identified from the pilot screen were tested to determine if they affected the action potential duration of atrial cardiomyocytes sensitized by the E375X mutation in KCNA5, and if they had effects on the action potential durations of wild type and primary atrial and ventricular cardiomyocytes. This proposal builds on data from the applicants, an established team from SBP (Drs. Colas and Larson) with basic biology and drug discovery expertise in the field and access to all necessary technologies. The overall goal of this proposal is to generate chemical biology research tools and starting points for new drugs. As the critical path assays are all in place, we anticipate we can rapidly obtain such probe molecules and start to explore their activity. Our future plans are to ultimately determine hits’ suitability for hit-to-lead activities, begin in vivo evaluation of lead compounds in animal models and eventually patients, and determine their cellular mechanism of action. This grant’s work product will serve as preliminary data for hit-to-lead (HTL) grant submissions and parent R01 grant submissions to pursue understanding of their biological mechanisms.

项目摘要 心房颤动（AF）是最普遍的心律不齐，在全球范围内遭受超过3300万人的痛苦和6人 在美国百万。 AF导致生活质量降低，中风和系统性的血栓主义，心力衰竭和 死亡率增加。特征是对AF及其并发症的处理，其并发症的特征是 通过不满意的结果和巨大的成本。获得的心脏病，心脏重塑，神经激素 因素，衰老和遗传特征都与AF的存在相关。快速，不协调的心房 腔室活动是由于作用在 脆弱的心肌底物，导致持续性心律不齐，其具有触发或持续电路的重复 分别进入或提早和/或延迟pe骨。我们最近开发了一部小说高 吞吐量动力学成像和分析平台以表征心肌细胞电生理特性 在单细胞分辨率下，该分辨率可用于在功能性人体上进行高吞吐量筛选（HTS） 源自IPS细胞产生的ID1编程心脏祖细胞的心房心肌细胞。我们的创新 是在表型筛选级联中的使用和相关测定的使用 心肌细胞电性能和节奏的未知，心房特异性调节剂。我们的假设是 方法最终将产生类似毒品的起点，以改善疾病的心血管 疗法。主要的HTS分析已以384孔格式完全优化，作为证明 测定准备就绪，已经筛选了400种化合物（Kolmogorov-Smirnov D统计> 0.1）。来自 鉴定了试点屏幕并在浓度响应实验中进行了确认并验证。电池 已经开发和试点的下游测定法以建立关键的路径测试漏斗。一些 测试了从试验屏幕上鉴定的化合物，以确定它们是否影响了动作电位持续时间 kCNA5中的E375X突变敏感的心房心肌细胞，如果它们对动作有影响 野生型和原发性心房和心室心肌细胞的潜在持续时间。该建议以数据为基础 来自申请人，来自SBP（Colas Dr.Colas和Larson）的成熟团队，具有基本的生物学和药物发现 该领域的专业知识并访问所有必要的技术。该提议的总体目标是生成 化学生物学研究工具和新药的起点。由于关键路径分析都到位，我们 预计我们可以迅速获得这种探针分子并开始探索它们的活性。我们未来的计划是 最终确定命中率对命中率活动的适用性，开始对动物中铅化合物的体内评估 模型，有时是患者，并确定其细胞作用机理。该赠款的工作产品将 作为命中率（HTL）赠款提交和父母R01赠款提交提交的初步数据（HTL）的初步数据 了解其生物学机制。