Sphingolipids in Diabetic Cardiomyopathy

糖尿病心肌病中的鞘脂

基本信息

批准号：
8761962
负责人：
Lauren Ashley Cowart
金额：
$ 37.38万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-18 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8761962
关键词：
Acids Address Affect American Anabolism Apoptosis Attenuated Autophagocytosis Biochemical Biochemistry Biology Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Catheterization Cell Nucleus Cell physiology Cells Ceramides Characteristics Clinical Complement Data Diabetes Mellitus Diet Disease Echocardiography Enzymes Fatty Acids Functional disorder Generations Geometry Goals Health Heart Heart failure Hypertrophy Individual Injury Insulin Resistance Left Ventricular Hypertrophy Light Lipids Measures Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mus Myocardium Nature Nuclear Obesity Outcome Pathway interactions Plasma Play Process Protein Isoforms Publications Publishing Regulation Risk Factors Role Scheme Signal Transduction Sphingolipids Testing Tissues Toxic effect Up-Regulation Work base diabetic diabetic cardiomyopathy dihydroceramide desaturase enzyme pathway feeding heart disease risk high risk improved in vivo insight lipid metabolism mitochondrial dysfunction novel prevent public health relevance response saturated fat translational approach

项目摘要

DESCRIPTION (provided by applicant):: Diabetics are at increased risk of heart disease from several factors including geometric and functional changes that occur independently of other risk factor; this is termed 'diabetic cardiomyopathy'. Mechanisms of this disease are not completely understood, but data increasingly support the notion that aberrant lipid metabolism contributes to this disease process. Among these metabolic changes are perturbations in sphingolipid synthesis; others and we have shown that blocking sphingolipid synthesis ameliorates many facets of diabetic cardiomyopathy. Sphingolipid metabolism comprises numerous enzymes, pathways, and products; teasing apart specific sphingolipids that mediate a specific process has proven challenging. Moreover, mechanisms by which these processes occur have been difficult to determine. We recently published that a specific enzyme of sphingolipid synthesis, Ceramide Synthase 5 (CerS5), mediated lipid- induced cardiomyocyte hypertrophy and autophagy. In a high saturated-fat feeding model in mice, which caused insulin resistance and obesity, sphingolipid biosynthesis was perturbed in heart. We observed sphingolipid-dependent cell hypertrophy, autophagy, and most importantly, cardiac dysfunction. New preliminary data implicate sphingolipids in mitochondrial damage and mitophagy, and also shed light on molecular mechanisms by which CerS5 causes autophagy. We have observed 1-nuclear accumulation of CerS5 and its product C14-ceramide, 2-CerS5-dependent accumulation of p53 in the nucleus, and 3- sphingolipid-dependent loss of mitochondrial reserve, and increase in mitophagy. Here we propose to dissect mechanisms for DbCM based on these initial findings, and using a combination of strategies including in vivo determinations o diastolic dysfunction in mice lacking CerS5, components of the mitophagy pathway, components of the macroautophagy pathway. As evidenced by our recent publications (Russo et al. 2012, J. Clin. Invest.; Russo et al 2013, J. Biol. Chem.), we are highly suited to address these questions that lie at the interface of sphingolipid biochemistry and cardiology. To facilitat this highly translational work we have enlisted cardiology and metabolism experts to complement our expertise in sphingolipid biochemistry, signaling, and analysis. These studies will reveal roles of these cell processes in diabetic cardiomyopathy, address the controversy surrounding the nature of autophagy in cardiac injury, specifically whether it is adaptive or deleterious, provide insights into sphingolipid-dependent mitochondrial dysfunction, which is especially important in the diabetic context, and finally reveal cell, biochemical, and molecular mechanisms of sphingolipid-dependent lipotoxicity in the heart.

描述（由申请人提供）：：糖尿病患者患心脏病的风险增加，原因有多种，包括独立于其他风险因素发生的几何和功能变化；这被称为“糖尿病心肌病”。这种疾病的机制尚不完全清楚，但数据越来越多地支持脂质代谢异常导致这种疾病过程的观点。这些代谢变化包括鞘脂合成的扰动；其他人和我们已经证明，阻断鞘脂合成可以改善糖尿病心肌病的许多方面。鞘脂代谢包含多种酶、途径和产物；事实证明，区分介导特定过程的特定鞘脂具有挑战性。此外，这些过程发生的机制一直难以确定。我们最近发表了一种鞘脂合成的特定酶，神经酰胺合成酶 5 (CerS5)，介导脂质诱导的心肌细胞肥大和自噬。在导致胰岛素抵抗和肥胖的小鼠高饱和脂肪喂养模型中，心脏中的鞘脂生物合成受到干扰。我们观察到鞘脂依赖性细胞肥大、自噬，最重要的是心脏功能障碍。新的初步数据表明鞘脂与线粒体损伤和线粒体自噬有关，并且还揭示了 CerS5 引起自噬的分子机制。我们观察到CerS5及其产物C14-神经酰胺的1-核积累、p53在细胞核中的2-CerS5依赖性积累、以及3-鞘脂依赖性线粒体储备损失和线粒体自噬的增加。在这里，我们建议根据这些初步发现剖析 DbCM 的机制，并使用多种策略的组合，包括体内测定缺乏 CerS5 的小鼠的舒张功能障碍、线粒体自噬途径的成分、巨自噬途径的成分。正如我们最近发表的出版物（Russo 等人，2012 年，J. Clin. Invest.；Russo 等人，2013 年，J. Biol. Chem.）所证明的那样，我们非常适合解决鞘脂生物化学和生物化学之间的这些问题。心脏病学。为了促进这项高度转化的工作，我们聘请了心脏病学和新陈代谢专家来补充我们在鞘脂生物化学、信号传导和分析方面的专业知识。这些研究将揭示这些细胞过程在糖尿病心肌病中的作用，解决围绕心脏损伤中自噬性质的争议，特别是它是适应性的还是有害的，提供对鞘脂依赖性线粒体功能障碍的见解，这在糖尿病背景下尤其重要，最终揭示心脏中鞘脂依赖性脂毒性的细胞、生化和分子机制。