"Glycosphingoiipids,Giycosyltransferases and Cardiovascular disease"

目前对神经鞘糖脂(GSL)在动脉粥样硬化中的作用知之甚少。 在西方世界，大约50%的人口患有心血管疾病(CVD)和死亡。我们观察到 GSL；乳糖基神经酰胺(LacCer)水平和LacCer合成酶(LCS)活性增加 人类动脉粥样硬化斑块，与可见的正常组织相比。我们的初步研究还表明， 动脉粥样硬化和血胆固醇水平的显著升高可以通过GSL合成来逆转 抑制剂(D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol；D-PDMP)在大鼠饮食模型中 兔高脂血症。我们的总体目标是确定抑制GSL合成是否可以改善 高脂血症/动脉粥样硬化载脂蛋白E(apoE-/-)小鼠模型中的动脉粥样硬化。并向 确定LCS质量是否可作为CVD的预后指标。 我们的具体目标是：1.确定D-PDMP对apoE-/-小鼠动脉粥样硬化的调节作用； 在此，D-PDMP预防和干预动脉粥样硬化的效果将在小鼠身上进行检验 喂食高脂饮食，测量以下指标：心功能、颈动脉内膜中层 增厚、动脉僵硬、脂类和脂蛋白。2.确定分子机制(S) 哪些D-PDMP调节动脉粥样硬化；影响GSL和胆固醇稳态的蛋白质有助于 将测量细胞增殖、黏附和血管生成。3.确定员工的具体角色 乳糖神经酰胺和LCS与动脉粥样硬化我们将合成新型LCS抑制剂，并测定它们的 预防/干预动脉粥样硬化的功效。4.量化LCS的质量并评估后- 正常和动脉粥样硬化小鼠心脏和动脉中的转录修饰。我们将开发小说 用酶联免疫吸附试验和质谱仪测定LCS质量和转录后修饰。 建议的研究肯定会证实抑制GSL的合成可以抑制动脉粥样硬化。会的 也证明了LCS可以成为开发药物以改善CVD和相关疾病的新靶点。 最后，这些研究将改变我们对GSL在健康和心血管疾病中的作用的看法。 相关性(请参阅说明)： 虽然关于胆固醇在心脏病中的作用已经知道很多，但我们对胆固醇的作用的了解 神经鞘糖脂在本病中的作用一直比较滞后。在这里，我们主张检验这样的假设：抑制 鞘糖脂合成可降低血胆固醇水平，改善动脉粥样硬化和 动物模型中的心脏病。我们的研究将为新型药物疗法在癌症中的应用奠定基础 人类自身的裂痕

Little is known about the role of glycosphingoiipids (GSL) in atherosclerosis, which contributes to cardiovascular disease (CVD) and death in ~50% of the population, in the western world. We have observed that the level of a GSL; lactosylceramide (LacCer) and the activity of LacCer synthase (LCS) is increased in human atherosclerotic plaques, as compared to visibly normal tissue. Our preliminary studies also show that atherosclerosis and a marked increase in the level of blood cholesterol can be reveresed by a GSL synthesis inhibitor (D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol; D-PDMP) in a dietary model of hyperlipidemia in rabbits. Our overall goal is to determine whether inhibiting GSL synthesis can ameliorate atherosclerosis in an apolipoprotien E(apoE-/-) mouse model of hyperlipidemia /atherosclerosis. And to determine whether LCS mass can serve as a prognostic marker in CVD. Our specific aims are: 1. To determine the efficacy of D-PDMP in regulating atherosclerosis in apoE-/- mice; herein, the efficacy of D-PDMP in preventing and interfering with atherosclerosis will be examined in mice fed a hyperlipidemic diet, and the following will be measured: cadiac function, carotid intima media thickeness, arterial stiffness, and lipid and lipoprotiens. 2. To determine the molecular mechansim(s) by which D-PDMP regulates atherosclerosis; proteins affecting GSL and cholesterol homeostasis contributing to cell proliferation adhesion and angiogenesis will be measured. 3.To determine the specific roles of Lactosylceramide and LCS in atherosclerosis. We will synthesize novel LCS inhibitors and determine their efficacy in preventing /interfering with atherosclerosis. 4. Quantify the mass of LCS and assess post- transcriptional modification in the heart and artery in normal and atherosclerotic mice. We will develop novel ELISA assays and use mass spectrometry to determine LCS mass and post transcriptional modifiactions. The proposed studies will definitely establish that inhibiting GSL synthesis can inhibit atherosclerosis. It will also prove that LCS can be a novel target for developming drugs to ameliorate CVD and related diseases. Finally, these studies will change our mind-set with regard to the role of GSL in health and CVD. RELEVANCE (See instructions): Although much is known about the role of cholesterol in heart disease, our knowledge about the role of glycosphingoiipids in this disease has lagged behind. Herein, we propse to test the hypothesis that inhibiting glycosphingolipid synthesis can decrease blood levels of cholesterol, and ameliorate atherosclerosis and heart disease in animal models. Our studies will lay the foundation for application of novel drug therapy to amfillnratft hfiart riisfiasft in man