Mechanisms of Ventricular Tachycardia in Lipotoxic Cardiomyopathy

描述（由申请人提供）：本建议书详细介绍了一个全面的5年培训计划，为我的职业发展在心血管研究。我已经计划了这个指导研究计划，以提供必要的学术研究的独立职业生涯的额外的科学培训。我将在生物化学，基因调控，细胞电生理学和体内生理学领域获得深入的经验，应用于心力衰竭和心律失常的动物模型。史蒂文马克思博士将成为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导者。该项目将与脂质和心肌代谢专家伊拉戈德堡博士合作进行。此外，由心血管科学家（Andrew Marks，Robert Kass和Fadi Akar博士）和管理员（Jamie Rubin博士）组成的咨询委员会将提供科学和职业建议。本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，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，这被认为是心力衰竭的病理生理学原因，心力衰竭是一种称为脂毒性心肌病的综合征。我们最近发现，脂毒性心肌病的小鼠模型，一种心脏特异性过表达PPAR 3的转基因小鼠，具有延长的QRS和QT间期，并且在2-8个月大时突然死于室性心动过速（VT）。PPAR 3是调节脂质和葡萄糖代谢的配体激活的转录因子。这些PPAR 3心脏过表达小鼠逐渐发展为收缩功能受损的扩张型心肌病，并具有细胞内脂质的异常积累，但猝死通常发生在HF发展之前。我们已经发现，这些细胞中的单个心肌细胞具有延长的动作电位时程，可能是由于钾电流减少。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，这是已知的促进VT。因此，这种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，其自然史概括了这些患者的常见死因。我的目标是：1。描述脂毒性心肌病中导致心律失常的细胞电生理异常2。描述脂毒性心肌病的心脏传导异常;探讨脂毒性心肌病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率和死亡率的主要原因之一。心源性猝死是导致HF患者死亡的原因之一，通常是由于室性心律失常。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，这被认为是心力衰竭的病理生理学原因，心力衰竭是一种称为脂毒性心肌病的综合征。本项目旨在通过动物模型来了解脂毒性心肌病的病理生理学，脂毒性心肌病导致心律失常和猝死。

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.