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项目总结 房颤是最常见的心律失常。心房颤动的终生风险随着 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 纤颤通常是一种进行性疾病，通常始于短暂的发作，然后发展到更长的时间。 如果没有药物或电击引起的心脏复律，则不会终止发作。成本和 随着美国人口老龄化和肥胖率上升，心房颤动的健康负担预计会上升 增加，从而突出了干预和治疗的必要性，可以减缓进展和减少 房颤的负担。心房颤动的总体目标：治疗机制 PPG的应用是将房颤基因组的发现转化回床边，专注于基因到 机制、基因对药物的作用以及基因与代谢和环境的相互作用。我们的中央 假说是，增加我们对涉及遗传、新陈代谢和 心房的结构变化将使我们能够准确定位可能的靶点，以实现更安全和更有效的治疗 战略。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将保持和传播诱导性 多能干细胞(IPSCs)，将IPSCs分化为房性或室性心肌细胞(a-ICM，v-ICM)， 从这些细胞中创造出工程化的心脏组织，并维持心房成纤维细胞。目标2将协调收缩， ICMS、EHTS和小鼠LA的代谢和结构表型。SC1为人类提供了独特的访问权限 A-ICMS以及a-EHTS，将使这一PPG上的所有调查人员能够在 协调高效的工作方式。虽然我们将重点放在a-ICM和a-EHTS上 我们还支持使用v-ICM和v-EHTS的研究，这些研究将有助于区分心房和心室 效果。我们在生成和维护人类ICM和EHTS方面的经验为 我们PPG内的项目使用这一尖端技术来测试创新假设。重要的是，使用 SC1对这些实验模型表型的专门知识，包括对收缩功能的评估， 线粒体呼吸、线粒体内容物、亚细胞结构和RNA的分离确保了一致性 跨多个模型、通过所有项目的方法，并使这些技术可供个人使用 这些实验室本来是不可行的。SC1消除了重复工作，并优化了 人员、设备和补给。SC1提供的独特专业知识将支持本PPG的目标 将AF基因组的发现转换回床边。