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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.

父COBRE奖（P20GM139763）的目标是支持研究项目负责人（RPL）