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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.

母公司Cobre奖(P20GM139763)的目标是支持研究项目负责人(RPL) 在科布雷的领导下，通过创造和统一资源，在细胞代谢领域实现科学独立-- 俄克拉荷马州细胞代谢研究支持中心(CMRO)。李志峰医生一直被由CMRO-Cobre作为RPL支持。李实验室创建了一个研究项目，调查新陈代谢如何调节心脏病的进展。在目前Cobre的支持下，Lee实验室探讨线粒体功能障碍和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，心律失常会增加患者的风险。心力衰竭、中风和猝死。在这项补充奖中，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/钙信号方面的合作，并一起研究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新陈代谢如何调节电/钙信号以促进心律失常，这一假说还没有得到严格和直接的检验。林志强医生训练有素在实验室研究小鼠模型中的电/钙信号并使用诱导的多能干细胞用于识别心律失常机制的平台。我们的试点数据使用心脏特有的线粒体功能障碍小鼠(Ndufs4-CKO)显示线粒体功能障碍增加了心脏对导致心律失常并促进猝死。我们发现在分离的心肌细胞中钙信号会发生改变来自心律失常的Ndufs4-CKO心脏。在这个增刊奖中，我们计划彻底描述变化的特征在这些心律失常的心脏中，线粒体的功能和代谢，以及电/钙信号。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子标测(EMAP)解剖空间特定的变化(心房和心室) LAM实验室提供的心律失常Ndufs4-CKO心脏。空间转录和代谢组学分析将使用靶向细胞和线粒体新陈代谢，可用于Lee实验室。通过将专业知识结合起来电/钙信号转导(LAM实验室)和新陈代谢(Lee实验室)，这一系列实验将提供将线粒体功能障碍与心律失常联系起来的重要机制靶点有待进一步研究。我们的长期目标是申请多PI R01拨款，分析详细的分子机制如何线粒体代谢调节心律失常中的电/钙信号。我们的试点数据已经支持可能的机制之一与线粒体改变NAD+依赖的代谢信号有关功能障碍，使钙处理蛋白失控(如CaMKII乙酰化)。互补的专业知识 Lee和LAM实验室将在发展我们的年轻研究计划和了解心律失常的新机制。