Center for Cellular Metabolism Research in Oklahoma

俄克拉荷马州细胞代谢研究中心

基本信息

批准号：
10853688
负责人：
Lijun Xia
金额：
$ 57.17万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-05 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10853688
关键词：
Acetylation Action Potentials Area Arrhythmia Award Biological Assay Blood Vessels Calcium Calcium Signaling Cardiac Cardiac Myocytes Cells Centers of Research Excellence Collaborations Complex Conscious Coupling Data Defect Delaware Diabetes Mellitus Disease Progression EFRAC Electrocardiogram Event Fibroblasts Foundations Functional disorder Genes Geometry Glucose Goals Grant Heart Heart Atrium Heart Diseases Heart failure Impairment Incidence Isoproterenol Kinetics Laboratories Laboratory Study Left Link Lipids Malignant - descriptor Maps Measures Medical Metabolic Metabolism Mitochondria Molecular Morphology Mus Neurons Obesity Oklahoma Osmosis Oxidation-Reduction Parents Patients Pattern Perfusion Phenotype Pilot Projects Predisposition Proteins Pump Research Research Project Grants Research Support Resources Risk Risk Factors Role Sedation procedure Series Signal Transduction Sodium-Calcium Exchanger Stress Stress Tests Stroke Sudden Death Surface System Telemetry Testing Tissues Training Transcript Universities Ventricular Ventricular Arrhythmia aqueous calmodulin-dependent protein kinase II cell type cellular targeting design diabetic cardiomyopathy experience experimental study heart metabolism hypertensive in vivo induced pluripotent stem cell live cell imaging metabolic phenotype metabolomics mitochondrial dysfunction mitochondrial metabolism mouse model new therapeutic target novel programs sudden cardiac death transcriptomics uptake

项目摘要

The goal of the parent COBRE award (P20GM139763) is to support research project leaders (RPL) to scientific independence in area of cellular metabolism by creating and unifying resources under the COBRE- supported Center of Cellular Metabolism Research in Oklahoma (CMRO). Dr. Chi Fung Lee has been supported by the CMRO-COBRE as a RPL. The Lee lab has created a research program that investigates how metabolism regulates heart disease progression. With the current COBRE support, the Lee lab is examining mechanisms by which mitochondrial dysfunction and NAD+ redox imbalance promotes diabetic cardiomyopathy. Patients with heart disease are associated with arrhythmias, which increase risks of patients to heart failure, stroke and sudden death. In this supplement award, the Lee lab seeks support to continue a collaboration with the Lam Lab at the University of Delaware on cardiac electrical/calcium signaling, and to together examine the mechanistic roles of mitochondrial dysfunction and metabolism in arrhythmogenesis. We aim to examine how mitochondrial metabolism regulates electrical/calcium signals to promote arrhythmias, a hypothesis that has not been rigorously and directly tested. Dr. Chi Keung Lam was well-trained in laboratories studying electrical/calcium signaling in mouse models and using induced pluripotent stem cell platforms to identify mechanisms of arrhythmias. Our pilot data using cardiac-specific mitochondrial dysfunction mice (Ndufs4-cKO) showed that mitochondrial dysfunction increases susceptibility of hearts to arrhythmias and promotes sudden death. We found that calcium signaling is altered in cardiomyocytes isolated from the arrhythmic Ndufs4-cKO hearts. In this supplement award, we plan to thoroughly characterize changes in mitochondrial function and metabolism, and electrical/calcium signaling in these arrhythmias hearts. To understand how mitochondrial dysfunction promotes atrial and ventricular arrhythmic events, we will dissect spatial-specific changes (atrial and ventricular) using state-of-the-art electrical mapping (eMapping) of the arrhythmic Ndufs4-cKO hearts available to the Lam lab. Spatial transcriptomic and metabolomic analyses targeting cellular and mitochondrial metabolism will be used, available to the Lee lab. By coupling the expertise of electrical/calcium signaling (Lam lab) and metabolism (Lee lab), this series of experiments will provide important mechanistic targets to be further explored linking mitochondrial dysfunction to arrhythmias. Our long-term goal is to apply for a multi-PIs R01 grant that dissects detailed molecular mechanisms how mitochondrial metabolism regulates electrical/calcium signaling in arrhythmias. Our pilot data already support one of the possible mechanisms in related to NAD+-dependent metabolic signaling altered by mitochondrial dysfunction to deregulate calcium handling proteins (e.g. CaMKII acetylation). The complementary expertise in the Lee and Lam labs will have synergistic effects in developing our young research programs and understanding novel mechanisms of arrhythmias.

母 COBRE 奖 (P20GM139763) 的目标是支持研究项目负责人 (RPL) 通过在 COBRE 下创建和统一资源，实现细胞代谢领域的科学独立性支持俄克拉荷马州细胞代谢研究中心 (CMRO)。李志峰博士曾由 CMRO-COBRE 作为 RPL 支持。李实验室创建了一个研究项目来调查新陈代谢如何调节心脏病的进展。在当前 COBRE 的支持下，Lee 实验室研究线粒体功能障碍和 NAD+ 氧化还原失衡促进糖尿病的机制心肌病。心脏病患者与心律失常有关，这会增加患者的风险导致心力衰竭、中风和猝死。在这个补充奖项中，李实验室寻求支持以继续与特拉华大学 Lam 实验室在心脏电/钙信号传导方面进行合作，并共同检查线粒体功能障碍和代谢在心律失常发生中的机制作用。我们的目标是研究线粒体代谢如何调节电/钙信号以促进心律失常，这一假设尚未经过严格和直接的检验。林志强博士训练有素在实验室研究小鼠模型中的电/钙信号传导并使用诱导多能干细胞识别心律失常机制的平台。我们使用心脏特异性线粒体的试点数据功能障碍小鼠（Ndufs4-cKO）表明，线粒体功能障碍会增加心脏对心律失常并促进猝死。我们发现分离的心肌细胞中钙信号传导发生了改变来自心律失常的 Ndufs4-cKO 心脏。在这个补充奖项中，我们计划彻底描述变化的特征线粒体功能和代谢，以及这些心律失常心脏中的电/钙信号传导。为了了解线粒体功能障碍如何促进房性和室性心律失常事件，我们将使用最先进的电映射 (eMapping) 剖析空间特定变化（心房和心室） Lam 实验室可用的心律失常 Ndufs4-cKO 心脏。空间转录组学和代谢组学分析将使用李实验室提供的针对细胞和线粒体代谢的药物。通过结合专业知识电/钙信号传导（Lam 实验室）和新陈代谢（Lee 实验室），这一系列实验将提供需要进一步探索将线粒体功能障碍与心律失常联系起来的重要机制目标。我们的长期目标是申请多 PI R01 资助，剖析详细的分子机制线粒体代谢调节心律失常中的电/钙信号传导。我们的试点数据已经支持与线粒体改变的 NAD+ 依赖性代谢信号相关的可能机制之一钙处理蛋白失调（例如 CaMKII 乙酰化）的功能障碍。互补的专业知识 Lee 和 Lam 实验室的人员将在发展我们的年轻研究项目和了解心律失常的新机制。