Sphingolipids in Diabetic Cardiomyopathy

描述(由申请人提供)：糖尿病患者心脏病风险增加的原因有几个，包括与其他风险因素无关的几何和功能变化；这被称为‘糖尿病心肌病’。这种疾病的发病机制尚不完全清楚，但越来越多的数据支持这样一种观点，即异常的脂代谢有助于这种疾病的发生。在这些代谢变化中，包括鞘脂合成的紊乱；其他的，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。鞘脂代谢包括许多酶、途径和产物；梳理出调节特定过程的特定鞘脂被证明是具有挑战性的。此外，这些过程发生的机制一直很难确定。我们最近发表了神经鞘脂合成的一种特殊酶，神经酰胺合成酶5(CerS5)，它介导了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高饱和脂肪喂养小鼠模型中，鞘脂的生物合成在心脏中受到干扰。我们观察到鞘磷脂依赖的细胞肥大、自噬，最重要的是，心功能障碍。新的初步数据表明鞘磷脂与线粒体损伤和有丝分裂吞噬有关，也阐明了CerS5导致自噬的分子机制。我们观察到1-CerS5及其产物C14-神经酰胺在细胞核内的聚集，2-CerS5依赖的P53在细胞核内的聚集，以及3-鞘磷脂依赖的线粒体储备的丧失，并增加了有丝分裂。在这里，我们建议基于这些初步发现，并使用多种策略的组合来剖析DbCM的机制，包括体内测定缺乏CerS5的小鼠的舒张期功能障碍，CerS5是有丝分裂吞噬途径的组成部分，是宏观自噬途径的组成部分。我们最近的出版物(Russo等人)证明了这一点。2012年，J.Clin。投资；Russo et al 2013，J.Biol。)，我们非常适合解决这些存在于鞘脂生物化学和心脏病学之间的问题。为了促进这项高度翻译的工作，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、信号传递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，提供对鞘磷脂依赖的线粒体功能障碍的见解，这在糖尿病的背景下尤其重要，并最终揭示鞘磷脂依赖的心脏脂毒性的细胞、生化和分子机制。

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.