The Role of Sphingolipid Metabolism in Obesity-Related Lipotoxic Cardiomyopathy

鞘脂代谢在肥胖相关脂毒性心肌病中的作用

• 批准号: 8784992
• 负责人: Stanley Walls
• 金额: $ 5.15万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784992
• 关键词: Affect; Animal Model; Apoptosis; Apoptotic; Arrhythmia; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Pathology; Cardiovascular Physiology; Cell Death; Cell Survival; Cells; Ceramides; Congenital Heart Defects; Data; Defect; Diet; Drosophila genus; Enzymes; Etiology; Exhibits; Fatty Acids; Functional disorder; Genes; Genetic; Genetic Models; Genetic screening method; Heart; Heart Hypertrophy; Human; Intervention; Knowledge; Leptin; Link; Lipids; Mammals; Measures; Membrane; Metabolic; Metabolic Marker; Metabolism; Modeling; Modification; Molecular; Mus; Mutation; Myocardial; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Play; Process; Pump; Reporting; Research; Risk; Role; Sphingolipids; Structure; Techniques; Triglycerides; Work; base; cardiogenesis; feeding; fly; heart dimension/size; heart function; improved; in vivo; lipoprotein lipase; loss of function; mouse model; mutant; novel; novel therapeutic intervention; overexpression; prevent; public health relevance; research study; sphingosine 1-phosphate; sphingosine kinase; sphingosine-1-phosphate lyase; tool; ventricular hypertrophy

DESCRIPTION (provided by applicant): Obesity and Type II Diabetes have been shown to adversely affect cardiac function. A signature set of cardiac defects arising from these conditions is generally referred to as lipotoxic cardiomyopathy (LCM). Common functional defects of LCM generally include cardiac hypertrophy, diastolic dysfunction, arrhythmia and loss of pumping power. Metabolic features of LCM include abnormal accumulation of various lipids in the heart including triglycerides, fatty acids and the bioactive sphingolipid (SL) ceramide. However, there is still a wide gap in our knowledge regarding whether ceramides and related SLs play a direct, active role in the induction or progression of lipotoxic cardiomyopathies. These questions have been difficult to answer due to the lack of a suitable genetic model. Additionally, reliable high-throughput techniques to identify and quantitate all SL subspecies (the sphingolipidome) have only recently emerged. Ceramide is well established for its role in promoting cell death (apoptosis). The SL sphingosine 1- phosphate (S1P) has been shown to play an opposing role, promoting cell survival. In this respect, the levels of ceramide and S1P act as a rheostat in regulating cell fate as well as a variety of other processes. Interestingly, preliminary data suggests that ceramide accumulation in flies induces classic hallmarks of LCM, while flies that also accumulate S1P are protected from LCM. Thus, this suggests that the ceramide: S1P rheostat may have a novel regulatory role in determining heart size, structure and function in LCM. Here, Drosophila will be used as a model organism to determine if direct accumulation of ceramide in the heart is sufficient to induce classic hallmarks of LCM. The first specific aim is to characterize the role of ceramide in induction of lipotoxic cardiomyopathy. The second specific aim is to characterize the role of sphingosine 1-phosphate (S1P) in mitigating lipotoxic cardiomyopathy. These studies will use both genetic and pharmacological approaches to manipulate the ceramide: S1P rheostat, and directly assess its effects in vivo on cardiac size, structure and function.

描述（由申请人提供）：肥胖和II型糖尿病已被证明会对心脏功能产生不利影响。由这些条件引起的心脏缺陷的特征集通常被称为脂毒性心肌病（LCM）。LCM常见的功能缺陷通常包括心脏肥大、舒张功能障碍、心律失常和泵送功率损失。LCM的代谢特征包括心脏中各种脂质的异常积累，包括甘油三酯、脂肪酸和生物活性鞘脂（SL）神经酰胺。然而，关于神经酰胺和相关SL是否在脂毒性心肌病的诱导或进展中发挥直接、积极的作用，我们的知识仍有很大的差距。由于缺乏合适的遗传模型，这些问题一直难以回答。此外，可靠的高通量技术，以确定和定量所有SL亚种（ 神经鞘脂组）最近才出现。 神经酰胺在促进细胞死亡（凋亡）中的作用已得到充分证实。SL鞘氨醇1-磷酸（S1 P）已被证明发挥相反的作用，促进细胞存活。在这方面，神经酰胺和S1 P的水平在调节细胞命运以及各种其他过程中起着变阻器的作用。有趣的是，初步数据表明，果蝇中的神经酰胺积累诱导LCM的经典标志，而也积累S1 P的果蝇则免受LCM的影响。因此，这表明，神经酰胺：S1 P变阻器可能有一个新的调节作用，在决定心脏的大小，结构和功能的LCM。 在这里，果蝇将被用作一个模式生物，以确定神经酰胺在心脏中的直接积累是否足以诱导LCM的经典标志。第一个具体目标是描述神经酰胺在诱导脂毒性心肌病中的作用。第二个具体目标是表征1-磷酸鞘氨醇（S1 P）在减轻脂毒性心肌病中的作用。这些研究将使用遗传和药理学方法来操纵神经酰胺：S1 P变阻器，并直接评估其对心脏大小，结构和功能的体内影响。