Engineered Heart Tissue and Atrial Phenotyping Scientific Core 1

工程心脏组织和心房表型科学核心 1

• 批准号: 10410645
• 负责人: David R Van Wagoner
• 金额: $ 25.17万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410645
• 关键词: Age; American; Applications Grants; Arrhythmia; Atrial Fibrillation; Back; Cardiac Myocytes; Cellular Structures; Citrate (si)-Synthase; Data; Development; Diabetes Mellitus; Doctor of Philosophy; Drug Exposure; Drug Interactions; Elderly; Electric Countershock; Ensure; Environment; Equipment and Supplies; Evaluation; Experimental Models; Fibroblasts; Functional disorder; Generations; Genes; Genetic; Genomics; Genus Hippocampus; Goals; Health; Heart; Heart Atrium; Human; Human Resources; Hypertension; Individual; Knowledge; Laboratories; Lead; Left; Maintenance; Measures; Metabolic; Metabolic stress; Metabolism; Methodology; Methods; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Monitor; Morphology; Mus; Muscle Cells; Obesity; Pharmaceutical Preparations; Phenotype; Population; Preventive; Procedures; Production; Program Research Project Grants; Property; Protocols documentation; RNA; Reproducibility; Research Institute; Research Personnel; Resolution; Respiration; Risk Factors; Scientist; Services; Shock; Smoking; Structure; Subcellular structure; Supporting Cell; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translating; Ventricular; cardiac tissue engineering; clinical application; cost; cost effective; embryonic stem cell; experience; experimental study; gene interaction; genome wide association study; in vivo; induced pluripotent stem cell; innovation; lifetime risk; novel; programs; service organization; stem cell differentiation; therapeutically effective; treatment program

SC1 PROJECT SUMMARY Atrial fibrillation is the most common cardiac arrhythmia. The lifetime risk of atrial fibrillation increases with advancing age and other risk factors that include obesity, smoking, hypertension, and diabetes mellitus. Atrial fibrillation is often a progressive condition, frequently beginning with brief episodes that progress to longer episodes that do not terminate without either drug- or electrical shock induced cardioversion. The cost and health burden of atrial fibrillation are expected to rise as the American population ages and the obesity rates increase, thus highlighting the need for interventions and therapies that can slow the progression and reduce the burden of atrial fibrillation. The overall goal of the Atrial Fibrillation Post-GWAS: Mechanisms to Treatment PPG application is to translate AF genomic discoveries back to the bedside, focusing on genes to mechanisms, genes to drugs, and interactions of genes with metabolism and environment. Our central hypothesis is that increasing our knowledge about molecular mechanisms involved in genetic, metabolic and structural changes in the atria will allow us to pinpoint possible targets for safer and more effective therapeutic strategies. The Engineered Heart Tissue and Atrial Phenotyping Scientific Core 1 (SC1) will provide support for all Projects in this PPG application via two aims. Aim 1 will maintain and propagate inducible pluripotent stem cells (iPSCs), differentiate iPSCs to atrial- or ventricular-like cardiomyocytes (a-iCM, v-iCM), from these create engineered heart tissues, and maintain atrial fibroblasts. Aim 2 will coordinate the contractile, metabolic, and structural phenotyping of iCMs, EHTs, and mouse LA. SC1 provides unique access to human a-iCMs, as well as a-EHTs that will enable all investigators on this PPG to achieve their scientific goals in a coordinated and efficient manner. While we focus on a-iCMs and a-EHTs for most of the studies proposed in the Program, we also support studies using v-iCMs and v-EHTs that will help differentiate atrial vs. ventricular effects. Our experience with generating and maintaining human iCMs and EHTs provides an opportunity for Projects within our PPG to use this leading-edge technology to test innovative hypotheses. Importantly, the use of SC1 expertise for the phenotyping of these experimental models, including evaluation of contractile function, mitochondrial respiration, mitochondrial content, subcellular structure, and isolation of RNA ensures uniform methodology across multiple models, through all projects, and makes these techniques available to individual laboratories that were otherwise not feasible. SC1 eliminates duplication of effort and optimizes the use of personnel, equipment, and supplies. The unique expertise provided by SC1 will support the goal of this PPG to translate AF genomic discoveries back to the bedside.

SC1 项目概要 心房颤动是最常见的心律失常。心房颤动的终生风险随着年龄的增长而增加 年龄增长和其他危险因素，包括肥胖、吸烟、高血压和糖尿病。心房 颤动通常是一种进行性病症，通常以短暂的发作开始，然后发展为更长的发作 如果没有药物或电击诱导的复律就不会终止的发作。成本和 随着美国人口老龄化和肥胖率增加，房颤的健康负担预计将增加 增加，从而强调需要采取干预措施和治疗来减缓进展并减少 心房颤动的负担。房颤 GWAS 后的总体目标：治疗机制 PPG应用是将AF基因组发现转化回临床，重点关注基因 机制、基因与药物以及基因与代谢和环境的相互作用。我们的中央 假设是增加我们对涉及遗传、代谢和代谢的分子机制的了解 心房的结构变化将使我们能够确定可能的目标，以实现更安全、更有效的治疗 策略。工程心脏组织和心房表型科学核心 1 (SC1) 将提供 通过两个目标支持此 PPG 应用程序中的所有项目。目标 1 将维持和传播诱导型 多能干细胞 (iPSC)，将 iPSC 分化为心房或心室样心肌细胞 (a-iCM、v-iCM)， 由此产生工程心脏组织并维持心房成纤维细胞。目标 2 将协调收缩， iCM、EHT 和小鼠 LA 的代谢和结构表型。 SC1 提供了对人类的独特访问 a-iCM 以及 a-EHT 将使该 PPG 的所有研究人员能够在 协调高效。虽然我们在 2017 年提出的大部分研究都关注 a-iCM 和 a-EHT 该计划，我们还支持使用 v-iCM 和 v-EHT 的研究，这将有助于区分心房与心室 影响。我们在生成和维护人类 iCM 和 EHT 方面的经验为 我们 PPG 内的项目使用这项领先技术来测试创新假设。重要的是，使用 SC1 专业知识用于这些实验模型的表型分析，包括收缩功能的评估， 线粒体呼吸、线粒体含量、亚细胞结构和 RNA 分离确保均匀 跨多个模型、贯穿所有项目的方法论，并使这些技术可供个人使用 否则不可行的实验室。 SC1 消除了重复工作并优化了使用 人员、设备和物资。 SC1 提供的独特专业知识将支持该 PPG 的目标： 将 AF 基因组发现应用到临床。