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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：
8828277
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/8828277
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 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.

描述(由申请者提供)：这份建议书详细说明了我在心血管研究领域的职业发展的5年综合培训计划。我计划了这个有指导的研究项目，以提供独立学术研究生涯所需的额外科学培训。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·马克思博士将成为我科学和事业发展的主要导师。马克思博士是心血管离子通道领域的领军人物。该项目将与血脂和心肌新陈代谢专家艾拉·戈德伯格博士合作进行。此外，一个由知名心血管科学家(安德鲁·马克斯博士、罗伯特·卡斯博士和法迪·阿卡尔博士)和一名管理人员(杰米·鲁宾博士)组成的咨询委员会将提供科学和职业建议。这一应用的中心假设是，心肌细胞脂质含量增加会导致离子通道和缝隙连接的异常调节，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备的增加，这被认为是心力衰竭的病理生理机制之一，这种综合征被称为脂中毒性心肌病。我们最近发现一种脂毒性心肌病小鼠模型，一种心脏特异性过表达PPAR3的转基因小鼠，延长了QRS和QT间期，并在2-8个月龄时突然死于室性心动过速(VT)。PPAR3是一种配体激活的转录因子，调节脂肪和葡萄糖代谢。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，细胞内脂质异常堆积，但猝死往往发生在心力衰竭发生之前。我们发现，来自这些细胞的单个心肌细胞动作电位持续时间延长，可能是由于钾电流减少所致。此外，心室缝隙连接的主要成分连接蛋白43在转录水平和蛋白质水平下调，这是已知的促进室速的因素。因此，这只小鼠是一种与糖尿病和肥胖症相关的日益常见的人类心脏病的独特模型，其自然病史概括了这些患者的常见死因。我的目的是：1.研究脂中毒性心肌病引起心律失常的细胞电生理异常；2.脂中毒性心肌病心脏传导异常的特征；3.探讨脂中毒性心肌病连接蛋白表达降低的分子机制。