iPSC-CM Modeling to Define Sodium-Calcium Dysfunction in Heart Failure

iPSC-CM 建模定义心力衰竭中的钠钙功能障碍

• 批准号: 10471338
• 负责人: Joseph C. Wu
• 金额: $ 51.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471338
• 关键词: Affect; Animal Model; Arrhythmia; BAG3 gene; Biological Assay; Calcium; Cellular Morphology; Clinical; Computer Models; Dantrolene; Data; Dilated Cardiomyopathy; Disease; Disease susceptibility; Drug Targeting; Economic Burden; Electrophysiology (science); Exhibits; Failure; Feedback; Fiber; Functional disorder; Gene Expression; Genes; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Heart failure; Homeostasis; Human; Impairment; Individual; Ion Channel; Lamin Type A; Link; Mechanics; Modeling; Molecular; Morbidity - disease rate; Muscle Cells; Mutation; National Heart, Lung, and Blood Institute; PDGFRB gene; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Positioning Attribute; Program Research Project Grants; Property; Protocols documentation; Public Health; Pump; Recording of previous events; Regulation; Risk; Role; RyR2; Severities; Signal Pathway; Signal Transduction; Sodium; Testing; Treatment Efficacy; United States National Institutes of Health; Variant; base; beta-adrenergic receptor; calmodulin-dependent protein kinase II; carvedilol; causal variant; clinically significant; drug response prediction; economic impact; genome editing; heart cell; high throughput screening; human stem cells; improved; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; inhibitor; insight; mortality; multi-electrode arrays; new therapeutic target; novel therapeutics; patch clamp; precision medicine; protein function; response; stem cell model; targeted treatment; therapeutic target; transcriptome; transcriptomics; voltage

Project Summary Heart failure (HF) continues to have a major clinical and economic burden with stagnation in new therapies over the past two decades. A significant barrier to improved therapies is the incomplete understanding of the role of Na+/Ca2+ dysregulation in HF and its contribution to electrical and mechanical dysfunction. Project 1 of this Program Project Grant (PPG) aims to elucidate the role of Na+/Ca2+ dysregulation in electro-mechanical dysfunction associated with (HF) using human induced pluripotent stem cell-derived cardiomyocytes (iPSC- CMs) based modeling. The Project will first phenotype DCM iPSC-CMs from individuals with heterogeneous causative variants and genome edited controls. Then the role of molecular pathways that regulate Na+/Ca2+ homeostasis will be examined in each of the iPSC-CMs to define major pathways implicated in electro- mechanical dysfunction and delineate genotype-specific mechanisms within DCM. Drug treatment cellular responses and gene expression profiles will then be used to define genotype-specific drug responses and novel drug targets. We are well positioned to achieve the project goals within five years. The ability to define genotype-based mechanisms and drug treatments within HF is well aligned with NIH and NHLBI goals of precision medicine models.

项目摘要 心力衰竭（HF）继续承担重大的临床和经济负担，并在新疗法中停滞不前 在过去的二十年中。改善疗法的重大障碍是对 Na+/Ca2+失调在HF中的作用及其对电气和机械功能障碍的贡献。项目1 该计划项目赠款（PPG）旨在阐明Na+/Ca2+功能障碍在电力力学中的作用 使用人类诱导的多能干细胞衍生的心肌细胞（IPSC- 基于CMS）建模。该项目将首先来自异质的人的DCM IPSC-CMS 因果变体和基因组编辑的对照。然后是调节Na+/Ca2+的分子途径的作用 将在每个IPSC-CMS中检查体内平衡，以定义与电力有关的主要途径 DCM内的机械功能障碍和划定基因型特异性机制。药物处理细胞 然后，将使用反应和基因表达曲线来定义基因型特异性药物反应和 新型药物靶标。我们在五年内实现项目目标的好处。定义的能力 HF内基于基因型的机制和药物治疗与NIH和NHLBI的目标很好地对准 精密医学模型。