Electrophysiology Scientific Core 2

电生理学科学核心 2

• 批准号: 10410646
• 负责人: KENNETH LAURITA
• 金额: $ 26.24万
• 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/10410646
• 关键词: Action Potentials; Age; Applications Grants; Arrhythmia; Atrial Fibrillation; Cell physiology; Clinical; Complement; Critiques; Data; Data Collection; Diagnosis; Dissociation; Doctor of Philosophy; Dyes; Electrocardiogram; Electrophysiology (science); Ensure; Equipment; Equipment and Supplies; Experimental Designs; Fluorescence Microscopy; Functional disorder; Fura-2; Genetic; Genomics; Goals; Heart; Heart Atrium; Human Resources; In Situ; Incidence; Individual; Ion Channel; Kinetics; Lead; Left atrial structure; Link; Maps; Measures; Membrane Potentials; Metabolic; Methodology; Methods; Microscopy; Mitochondria; Molecular; Monitor; Mus; Muscle Cells; Obesity; Optics; Outcome; Phenotype; Population; Predisposition; Preparation; Preventive; Procedures; Production; Program Research Project Grants; Property; Reactive Oxygen Species; Regulation; Reproducibility; Research Institute; Research Personnel; Resolution; Right atrial structure; Risk; Sampling; Scientist; Services; Stroke; Sum; System; Techniques; Technology; Testing; Therapeutic; base; cardiac tissue engineering; cardiovascular risk factor; clinical application; cost effective; cost efficient; design; drug discovery; experimental study; genome wide association study; innovation; mitochondrial membrane; mortality; patch clamp; programs; response; stressor; therapeutically effective; voltage; voltage sensitive dye

SC2 PROJECT SUMMARY Atrial fibrillation (AF) is the most common arrhythmia and a major risk factor for cardiovascular mortality and stroke. Incidence of AF is further increasing due to the rise in obesity and age of the population, factors closely related to AF risk and progression. Despite significant advances in AF diagnosis and management, treatment and clinical outcomes remain poor and more than a decade has passed since the last AF drug discovery. The overall goal of this PPG application is to use genetic/genomic findings to identify preventative and therapeutic strategies for AF and develop them towards clinical application. Our central hypothesis is that increasing the understanding of 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. Scientific Core 2 (SC2): Electrophysiology Core will support the overall goal of the PPG and test program hypotheses as follows: Aim 1. Routine and reliable acquisition of ECG data for serial assessment of AF progression and burden, Aim 2: Optical mapping of mice atria and engineered heart tissue (EHT) for linking cellular pathophysiology with mechanisms of AF, Aim 3: Enzymatic isolation of mouse atrial myocytes for electrophysiologic, ion channel and Ca2+ cycling studies. Collectively, the isolated myocyte studies combined with optical mapping will provide important mechanistic links between cellular pathophysiology, AF in situ, and the progresion of AF in serial ECGs. We will leverage the capabilities and expertise of this Core to allow Project investigators to systematically integrate electrophysiological and cellular findings with genetic observations. This allows an assessment of differences in susceptibility of the atria to metabolic or other stressors that Projects will be studying as important contributors to AF initiation and progression. Importantly, use of the Core for the acquisition and analysis of ECGs, optical mapping (mouse atria and EHTs), and characterization of Ca2+, action potential, and ion channel dynamics in isolated myocytes ensures uniform methodology that will strengthen the individual Projects of this PPG. Furthermore, metabolic dynamics measured in an electrophysiological context herein, will complement the same measured in a metabolic context (Scientific Core 1). This Core will provide in-depth intellectual input to support Projects with experimental design, execution and coordination of experiments, and centralization for data gathering, thereby promoting interaction and integration between Projects beyond merely providing a service. Finally, this core eliminates duplication of effort and optimizes the use of personnel, equipment, and supplies, which enables all Projects on this PPG to achieve their scientific goals in an organized and cost-efficient manner. In sum, the services provide by this core to the Projects will help advance the understanding of the pathophysiology of AF, thereby supporting the main goal of this PPG to identify preventive and therapeutic strategies for AF and advance them towards clinical application.

SC2项目总结 心房颤动（AF）是最常见的心律失常，也是心血管死亡的主要危险因素， 中风由于肥胖和人口年龄的增加，AF的发病率进一步增加， 与AF风险和进展相关。尽管房颤的诊断和治疗取得了重大进展， 临床结果仍然很差，并且自上一次AF药物发现以来已经过去了十多年。的 本PPG应用的总体目标是使用遗传/基因组发现来确定预防和治疗 并将其推向临床应用。我们的核心假设是， 对心房遗传、代谢和结构变化的分子机制的了解， 使我们能够确定更安全和更有效的治疗策略的可能目标。科学核心2 (SC2)：电生理核心将支持PPG和测试程序假设的总体目标， 目标1.常规和可靠的ECG数据采集，用于AF进展的系列评估， 目的2：小鼠心房和工程心脏组织（EHT）的光学标测，用于连接细胞 AF的病理生理学机制，目的3：小鼠心房肌细胞的酶分离， 电生理、离子通道和Ca 2+循环研究。总的来说，分离的肌细胞研究结合了 光学标测将提供细胞病理生理学、原位AF和 连续心电图中房颤的进展。我们将利用该核心的能力和专业知识， 项目研究人员将电生理学和细胞发现与遗传学相结合， 意见。这允许评估心房对代谢或其他疾病的敏感性的差异。 项目将研究的压力因素是房颤发生和进展的重要因素。重要的是， 使用Core采集和分析ECG、光学标测（小鼠心房和EHT），以及 分离的肌细胞中的Ca 2+、动作电位和离子通道动力学的表征确保了均匀的 这将加强本PPG的个别项目的方法。此外，代谢动力学 在本文的电生理学背景下测量，将补充在代谢环境中测量的相同测量。 科学核心1（Scientific Core 1）该核心将提供深入的智力投入，以支持项目， 实验设计，实验的执行和协调，以及数据收集的集中化，从而 促进项目之间的互动和整合，而不仅仅是提供服务。最后，这个核心 消除重复劳动，优化人员、设备和供应的使用， 关于这一项目规划补助金的项目，以有组织和具有成本效益的方式实现其科学目标。总之， 该中心为项目提供的服务将有助于促进对AF病理生理学的理解， 从而支持本PPG的主要目标，即确定AF的预防和治疗策略， 将其推向临床应用。