Mechanisms of Ventricular Tachycardia in Lipotoxic Cardiomyopathy

脂毒性心肌病室性心动过速的机制

基本信息

批准号：
8646980
负责人：
John Pearce Morrow
金额：
$ 13.11万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-12 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646980
关键词：
Action Potentials Administrator Advisory Committees Age-Months Animal Model Antibodies Area Arrhythmia Arrhythmogenic Right Ventricular Dysplasia Biochemistry Calcium Channel Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Cause of Death Cells Cessation of life Collaborations Connexin 43 Connexins Coronary Arteriosclerosis Data Diabetes Mellitus Dilated Cardiomyopathy Disease Down-Regulation Electrophysiology (science)Functional disorder Gap Junctions Gene Expression Profiling Gene Expression Regulation Genetic Transcription Heart Heart Diseases Heart failure Human Hypertension Immunoblotting Immunohistochemistry Individual Integral Membrane Protein Intracellular Accumulation of Lipids Ion Channel Ligands Lipids Maps Measures Mediating Mentors Messenger RNA Metabolism Modeling Molecular Morbidity - disease rate Mus Myocardial Natural History Obesity Optics Patch-Clamp Techniques Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phosphorylation Physiology Post-Translational Protein Processing Potassium Potassium Channel Proteins Regulation Research Risk Rodent Model Scientist Sodium Channel Sudden Death Syndrome Tissues Training Training Programs Transgenic Mice Up-Regulation Ventricular Ventricular Arrhythmia Ventricular Tachycardia activating transcription factor base biological adaptation to stress cDNA Arrays career career development db/db mouse diabetic diabetic patient endoplasmic reticulum stress experience glucose metabolism in vivo interest lipid metabolism mRNA Stability mortality mouse model overexpression prevent programs protein expression public health relevance sudden cardiac death

项目摘要

DESCRIPTION (provided by applicant): This proposal details a comprehensive 5-year training program for my career development in cardiovascular research. I have planned this mentored research program to provide the additional scientific training necessary for an independent career in academic research. I will gain in-depth experience in the areas of biochemistry, gene regulation, cellular electrophysiology, and in vivo physiology as applied to animal models of heart failure and arrhythmias. Dr. Steven Marx will by my primary mentor for scientific and career development. Dr. Marx is a leader in the field of cardiovascular ion channels. The project will be performed in collaboration with Dr. Ira Goldberg, an expert in lipids and myocardial metabolism. In addition, an advisory committee of established cardiovascular scientists (Drs. Andrew Marks, Robert Kass, and Fadi Akar) and an administrator (Dr. Jamie Rubin) will provide scientific and career advice. The central hypothesis of this application is that increased cardiac myocyte lipid content leads to abnormal regulation of ion channels and gap junctions, promoting arrhythmia. Increased cardiac myocyte lipid stores are observed in obese and diabetic patients and this is proposed to contribute to the pathophysiology of heart failure, a syndrome termed lipotoxic cardiomyopathy. We have recently found that a mouse model of lipotoxic cardiomyopathy, a transgenic mouse with cardiac-specific over expression of PPAR3, has prolonged QRS and QT intervals, and dies suddenly at 2-8 months of age from ventricular tachycardia (VT). PPAR3 is a ligand-activated transcription factor that regulates lipid and glucose metabolism. These PPAR3 cardiac over expression mice gradually develop a dilated cardiomyopathy with impaired systolic function and have abnormal accumulation of intracellular lipids, but sudden death often occurs before HF develops. We have found that individual cardiac myocytes from these cells have prolonged action potential duration, probably from reduced potassium current. Further, connexin 43, the main component of the ventricular gap junction, is down regulated at the transcriptional level and the protein level, which is known to promote VT. This mouse is thus a unique model of an increasingly common form of human heart disease associated with diabetes and obesity, with a natural history that recapitulates a common cause of death in these patients. My aims are: 1. To characterize the abnormal cellular electrophysiology leading to arrhythmias in lipotoxic cardiomyopathy 2. To characterize abnormal cardiac conduction in lipotoxic cardiomyopathy, and 3. To determine the molecular mechanisms of reduced connexin expression in lipotoxic cardiomyopathy. PUBLIC HEALTH RELEVANCE: Heart failure is one of the leading causes of morbidity and mortality in the USA. Sudden cardiac death is responsible for up to 50% of deaths among patients with HF and is often due to ventricular arrhythmias. Diabetes and obesity are associated with an increased risk of cardiomyopathy and heart failure. Increased cardiac myocyte lipid stores are observed in obese and diabetic patients and this is proposed to contribute to the pathophysiology of heart failure, a syndrome termed lipotoxic cardiomyopathy. This project seeks to understand the pathophysiology of lipotoxic cardiomyopathy that leads to arrhythmias and sudden death by using animal models.

描述（由申请人提供）：该提案详细介绍了我在心血管研究领域的职业发展的全面的 5 年培训计划。我计划了这个指导性研究计划，为学术研究的独立职业提供必要的额外科学培训。我将在生物化学、基因调控、细胞电生理学和应用于心力衰竭和心律失常动物模型的体内生理学领域获得深入的经验。史蒂文·马克思博士将是我科学和职业发展的主要导师。马克思博士是心血管离子通道领域的领军人物。该项目将与脂质和心肌代谢专家 Ira Goldberg 博士合作进行。此外，由资深心血管科学家（安德鲁·马克斯博士、罗伯特·卡斯和法迪·阿卡尔博士）和管理员（杰米·鲁宾博士）组成的咨询委员会将提供科学和职业建议。该申请的中心假设是心肌细胞脂质含量增加导致离子通道和间隙连接的异常调节，从而促进心律失常。在肥胖和糖尿病患者中观察到心肌细胞脂质储存增加，这被认为有助于心力衰竭（一种称为脂毒性心肌病的综合征）的病理生理学。我们最近发现脂毒性心肌病小鼠模型，即心脏特异性过度表达 PPAR3 的转基因小鼠，其 QRS 和 QT 间期延长，并在 2-8 个月大时因室性心动过速 (VT) 突然死亡。 PPAR3 是一种配体激活的转录因子，可调节脂质和葡萄糖代谢。这些PPAR3心脏过度表达的小鼠逐渐发展为扩张型心肌病，收缩功能受损，细胞内脂质异常积累，但在心力衰竭发生之前常常发生猝死。我们发现这些细胞中的单个心肌细胞具有延长的动作电位持续时间，可能是由于钾电流减少。此外，心室间隙连接的主要成分连接蛋白43在转录水平和蛋白质水平上下调，已知其可促进VT。因此，这种小鼠是一种与糖尿病和肥胖相关的日益常见的人类心脏病的独特模型，其自然史概括了这些患者的常见死因。我的目标是： 1. 表征脂毒性心肌病中导致心律失常的异常细胞电生理学特征 2. 表征脂毒性心肌病中的异常心脏传导，以及 3. 确定脂毒性心肌病中连接蛋白表达减少的分子机制。公共卫生相关性：心力衰竭是美国发病和死亡的主要原因之一。心力衰竭患者死亡的 50% 是由心源性猝死造成的，通常由室性心律失常引起。糖尿病和肥胖与心肌病和心力衰竭的风险增加有关。在肥胖和糖尿病患者中观察到心肌细胞脂质储存增加，这被认为有助于心力衰竭（一种称为脂毒性心肌病的综合征）的病理生理学。该项目旨在通过使用动物模型来了解导致心律失常和猝死的脂毒性心肌病的病理生理学。