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）：该建议详细介绍了我在心血管研究中的职业发展的全面五年培训计划。我已经计划了这项指导的研究计划，以提供学术研究独立职业所需的其他科学培训。我将在生物化学，基因调节，细胞电生理学和体内生理学领域获得深入的经验，以应用于心力衰竭和心律不齐的动物模型。史蒂文·马克思（Steven Marx）博士将由我的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导者。该项目将与脂质和心肌代谢专家Ira Goldberg博士合作进行。此外，成熟的心血管科学家（Andrew Marks博士，Robert Kass和Fadi Akar博士）和管理员（Jamie Rubin博士）将提供科学和职业建议。该应用的中心假设是，心肌细胞脂质含量增加会导致离子通道和间隙连接的异常调节，从而促进心律不齐。在肥胖和糖尿病患者中观察到心肌细胞脂质储存量增加，这被提出有助于心力衰竭的病理生理学，这是一种称为脂肪毒性心肌病的综合征。我们最近发现，脂肪毒性心肌病的小鼠模型是一种具有心脏特异性PPAR3表达的转基因小鼠，其QRS和QT间隔延长了，并且在2-8个月大时从心室tachyarcardia（VT）突然死亡。 PPAR3是调节脂质和葡萄糖代谢的配体激活转录因子。这些表达小鼠的PPAR3心脏逐渐发展出具有收缩功能受损并具有异常的细胞内脂质积累的扩张性心肌病，但是在HF发展之前，猝死经常发生。我们发现，来自这些细胞的单个心肌细胞具有延长的作用潜在持续时间，可能是由于钾电流降低而产生的。此外，在转录水平和蛋白质水平上调节了脑间隙连接的主要成分连接素43，已知可以促进VT。因此，该小鼠是与糖尿病和肥胖相关的越来越常见的人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。我的目的是：1。表征异常的细胞电生理学，导致脂肪毒性心肌病的心律不齐2。表征脂肪毒性心肌病中异常心脏传导的表征，3。确定脂质毒性毒性毒性毒性减少的肌瘤表达的分子力学。公共卫生相关性：心力衰竭是美国发病率和死亡率的主要原因之一。心脏猝死导致HF患者中多达50％的死亡，并且通常是由于心室心律不齐。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量增加，这被提出有助于心力衰竭的病理生理学，这是一种称为脂肪毒性心肌病的综合征。该项目旨在了解脂肪毒性心肌病的病理生理学，从而通过使用动物模型导致心律不齐和猝死。