Sphingolipid mediators in atherogenesis

参见说明）： 磷脂鞘磷脂（SM）被认为是一个重要的调节剂的发病机制， 然而，与我们对胆固醇在血管疾病中的作用的理解相反， 在这方面的了解是有限的。SM的代谢释放生物活性介质，如鞘氨醇1- 磷酸盐（S1 P）。该PPG支持的研究表明，S1 P与血管系统的相互作用 是细胞环境和受体特异性的。我们最近的研究表明，缺乏S1 p2 r基因的小鼠表现出 在Apoe-/-背景下显著抑制动脉粥样硬化。微阵列分析实验显示， S1 P2 R信号传导对于caspase 11的表达是必需的，caspase 11是一种炎性小体特异性蛋白酶， 参与炎性细胞因子IL-1f 3和IL-18的分泌。这些数据使我们能够提出， 髓腔中的S1 P2 R信号传导对动脉粥样硬化斑块的进展至关重要 通过调节炎性小体的功能。因此，中心假设是： 动脉粥样硬化斑块以及自分泌信号激活髓样S1 PRs并调节 巨噬细胞表型和命运。具体地说，巨噬细胞S1 P2 R维持病理性血管 通过调节炎性小体特异性caspase-11的表达来调节炎症。 第一个目标将集中在巨噬细胞中S1 P2 R信号传导如何调节炎性小体功能， 细胞因子释放第二个目的将测试巨噬细胞S1 P2 R/半胱天冬酶-11途径是否是必需的和/或 足以抑制Apoe敲除小鼠的动脉粥样硬化斑块发展。第三，我们会探讨 假设抗炎S1 P1 R拮抗促炎受体-S1 P2 R， S1 P3 R在动脉粥样硬化过程中微调巨噬细胞反应。 预计这些数据将增强我们对鞘脂信号传导作用的理解， 动脉粥样硬化此外，从本研究中获得的知识可能有助于作为一种新的控制方法 动脉粥样硬化使用S1 P受体为基础的药理学工具。 相关性（参见说明）： 动脉粥样硬化或动脉硬化会导致心脏病发作。我们发现一种特殊的脂质介质 一种叫做鞘氨醇1-磷酸（S1 P）的物质激活动脉粥样硬化斑块中巨噬细胞上的受体 调节炎症我们建议在小鼠模型中充分定义这种新的机制， 动脉粥样硬化这项工作可能会导致发现新的药物来阻止心脏病。

Seeinstructions): The phospholipid sphingomyelin (SM) is thought to be a significant regulator of pathogenesis of atherosclerosis; however, in contrast to our understanding of the role of cholesterol in vascular disease, our understanding in this area is limited. Metabolism of SM releases bioactive mediators such as sphingosine 1- phosphate (S1P). Studies supported by this PPG have shown that S1P interaction with the vascular system is cell context- and receptor-specific. Our recent studies show that mice that lack the S1p2r gene exhibit marked suppression of atherosclerosis in the Apoe-/- background. Microarray profiling experiments revealed that S1P2R signaling is essential for the expression of caspase 11, an inflammasome-specific protease involved in the secretion of the inflammatory cytokines IL-1f3 and IL-18. These data allow us to propose that S1P2R signaling within the myeloid compartment is critical for the progression of the atherosclerotic plaque by the regulation of inflammasome function. Thus the central hypothesis is : Enhanced production of S1P in the atherosclerotic plaque as well as autocrine signaling activates myeloid S1PRs and regulates macrophage phenotype and fate. Specifically, macrophage S1P2R sustains pathologic vascular inflammation by regulation of expression of inflammasome-specific caspase-11. The first aim will focus on how S1P2R signaling in the macrophage regulates inflammasome function and cytokine release. The second aim will test if macrophage S1P2R/ caspase-11 pathway is necessary and/or sufficient in atherosclerotic plaque development of the Apoe null mouse. Thirdly, we will explore the hypothesis that the anti-inflammatory S1P1R antagonizes the proinflammatory receptors -S1P2R and S1P3R to fine-tune the macrophage responses during atherosclerosis. These data are anticipated to enhance our understanding of the role of sphingolipid signaling in atherosclerosis. Furthermore, knowledge gained from this study maybe useful as a new approach to control atherosclerosis using S1P receptor-based pharmacological tools. RELEVANCE (See instructions): Atherosclerosis, or hardening of arteries, causes heart attacks. We have found that a specific lipid mediator called sphingosine 1-phosphate (S1P) activates its receptor on macrophages in the atherosclerotic plaque and regulates inflammation. We propose to fully define this novel mechanism in mouse models of atherosclerosis. This work could lead to the discovery of new agents to block heart disease.