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: 10646343
• 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/10646343
• 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; Elderly; Electric Countershock; Ensure; Environment; Equipment; Evaluation; Experimental Models; Fibroblasts; Functional disorder; Generations; Genes; Genetic; Genomics; Genus Hippocampus; Goals; Health; Heart; Heart Atrium; Human; Human Resources; Hypertension; Individual; Intervention; 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; 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; 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项目摘要 心房颤动是最常见的心律失常。随着房颤的终身风险随着 促进年龄和其他危险因素，包括肥胖，吸烟，高血压和糖尿病。心房 纤颤通常是一种渐进状态，通常从简短的发作开始，逐渐发展到更长的时间 没有药物或电击引起的心脏version的发作不会终止的发作。成本和 随着美国人口的年龄和肥胖率，预计心房颤动的健康负担将增加 增加，从而强调需要减慢进展并减少干预措施和疗法的需求 房颤的负担。 GWAS后心房颤动的总体目标：治疗机制 PPG应用是将AF基因组发现转移回床边，重点是基因 机制，药物基因以及基因与代谢和环境的相互作用。我们的中心 假设是，增加了我们对涉及遗传，代谢和涉及分子机制的知识 心房的结构变化将使我们能够指出可能更安全，更有效治疗的可能目标 策略。设计的心脏组织和心房表型科学核心1（SC1）将提供 通过两个目标支持本PPG应用程序中的所有项目。 AIM 1将维持并传播诱导 多能干细胞（IPSC）将IPSC与心房或心室样心肌细胞（A-ICM，V-ICM）区分开 通过这些创建工程性的心脏组织，并保持心房成纤维细胞。 AIM 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-ICMS以及A-EHT将使所有PPG的研究人员都能实现其科学目标 协调和高效的方式。虽然我们专注于A-ICM和A-EHTS 该程序，我们还支持使用V-ICM和V-EHT的研究，这些研究将有助于区分房屋与心室 效果。我们在生成和维护人类ICM和EHT方面的经验为 我们的PPG项目中使用这种领先技术来检验创新的假设。重要的是，使用 这些实验模型表型的SC1专业知识，包括评估收缩功能， 线粒体呼吸，线粒体含量，亚细胞结构和RNA的分离确保均匀 通过所有项目跨多个模型的方法，并使这些技术可用于个人 否则不可行的实验室。 SC1消除了​​努力的重复，并优化了 人员，设备和用品。 SC1提供的独特专业知识将支持该PPG的目标 将AF基因组发现翻译回床边。