Mechanisms of Ventricular Tachycardia in Lipotoxic Cardiomyopathy

脂毒性心肌病室性心动过速的机制

• 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
• 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

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）：这份提案详细介绍了我在心血管研究方面的职业发展的一个全面的5年培训计划。我已经计划了这个受指导的研究项目，为独立从事学术研究提供必要的额外科学训练。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·马克思博士将是我在科学和职业发展方面的主要导师。马克思博士是心血管离子通道领域的领军人物。该项目将与血脂和心肌代谢专家Ira Goldberg博士合作进行。此外，由知名心血管科学家组成的咨询委员会(dr。安德鲁·马克斯、罗伯特·卡斯和法迪·阿卡尔)和一位管理人员（杰米·鲁宾博士）将提供科学和职业建议。本应用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，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，这被认为是导致心力衰竭的病理生理学，一种称为脂毒性心肌病的综合征。我们最近发现脂毒性心肌病小鼠模型，一种心脏特异性PPAR3过表达的转基因小鼠，QRS和QT间期延长，并在2-8月龄时因室性心动过速（VT）突然死亡。PPAR3是一种配体激活的转录因子，调节脂质和葡萄糖代谢。这些PPAR3心脏过表达小鼠逐渐发展为扩张型心肌病，收缩功能受损，细胞内脂质异常积聚，但猝死往往发生在HF发生之前。我们发现这些细胞中的单个心肌细胞动作电位持续时间延长，可能是由于钾电流的减少。此外，连接蛋白43，心室间隙连接的主要成分，在转录水平和蛋白质水平下调，已知可促进室速。因此，该小鼠是与糖尿病和肥胖相关的日益常见的人类心脏病形式的独特模型，其自然史概括了这些患者的常见死亡原因。我的目标是：1；目的探讨脂毒性心肌病致心律失常的细胞电生理异常。2 .探讨脂毒性心肌病的心脏传导异常特征；探讨脂毒性心肌病中连接蛋白表达降低的分子机制。