Sphingolipid mediators in atherogenesis

动脉粥样硬化形成中的鞘脂介质

• 批准号: 7662907
• 负责人: Timothy Tun Hla
• 金额: $ 48.75万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-26 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662907
• 关键词: Accounting; Address; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Autocrine Communication; Biochemical; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Caspase; Cell membrane; Cells; Cholesterol; Cholesterol Homeostasis; Coagulation Process; Complex; Data; Dendritic Cells; Development; Dominant-Negative Mutation; Etiology; Exhibits; GTP-Binding Proteins; Gene Expression; Genes; H218 Protein; Heart Diseases; Hematopoietic; Hematopoietic stem cells; High Density Lipoproteins; Human; Hypoxia; Immune system; Inflammation; Inflammatory; Inflammatory Response; Instruction; Interleukin-18; Knockout Mice; Knowledge; Laboratories; Lead; Lipoproteins; Mediating; Mediator of activation protein; Membrane Microdomains; Messenger RNA; Metabolism; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; New Agents; PTEN gene; Pathogenesis; Pathologic; Pathway interactions; Peptide Hydrolases; Phenotype; Phospholipids; Phosphoric Monoester Hydrolases; Plasma; Production; Receptor Signaling; Regulation; Role; Signal Transduction; Sphingolipids; Sphingomyelinase; Sphingomyelins; Sphingosine-1-Phosphate Receptor; Stem cells; Stimulus; System; Testing; Therapeutic; Translational Regulation; Vascular Diseases; Vascular Permeabilities; Vascular System; Work; atherogenesis; base; cytokine; essential phospholipids; expression vector; in vivo; lipid mediator; macrophage; mouse model; mutant; novel; novel strategies; receptor; receptor coupling; research study; response; retinal angiogenesis; rho; rho GTP-Binding Proteins; sphingosine 1-phosphate; sphingosine kinase; tool; trafficking; vascular inflammation

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.

请参阅说明)： 磷脂鞘磷脂(SM)被认为是糖尿病发病的重要调节因子。 动脉粥样硬化；然而，与我们对胆固醇在血管疾病中的作用的理解相反，我们的 在这方面的理解是有限的。SM的代谢释放生物活性介质，如鞘氨醇-1- 磷酸盐(S1P)。由PPG支持的研究表明，S1P与血管系统相互作用 是特定于细胞环境和受体的。我们最近的研究表明，缺乏S1p2r基因的小鼠表现出 在APOE-/-背景中显著抑制动脉粥样硬化。微阵列图谱实验揭示 S1P2R信号对炎症体特异性蛋白水解酶caspase 11的表达至关重要 参与炎性细胞因子IL-1f3和IL-18的分泌。这些数据使我们能够提出 髓鞘内的S1P2R信号在动脉粥样硬化斑块的进展中起关键作用 通过对炎性小体功能的调节。因此，中心假设是：S1P在 动脉粥样硬化斑块和自分泌信号激活髓系S1PR并调节 巨噬细胞的表型和命运。具体而言，巨噬细胞S1P2R支持病理性血管 通过调节炎症体特异性caspase-11的表达来实现炎症。 第一个目标将集中在巨噬细胞中的S1P2R信号如何调节炎症体功能和 细胞因子的释放。第二个目标将测试巨噬细胞S1P2R/caspase-11途径是否必要和/或 足以抑制APOE基因缺失小鼠的动脉粥样硬化斑块的形成。第三，我们将探讨 假设抗炎S1P1R拮抗促炎受体-S1P2R和 S1P3R在动脉粥样硬化期间微调巨噬细胞的反应。 这些数据有望增强我们对鞘脂信号在脑内的作用的理解。 动脉硬化。此外，从这项研究中获得的知识可能作为一种新的控制方法有用。 使用基于S1P受体的药理学工具研究动脉粥样硬化。 相关性(请参阅说明)： 动脉粥样硬化或动脉硬化会导致心脏病发作。我们发现一种特定的脂质介体 1-磷酸鞘氨醇(S1P)激活动脉粥样硬化斑块中巨噬细胞上的S1P受体 并调节炎症。我们建议在小鼠模型中充分定义这一新的机制。 动脉硬化。这项工作可能会导致发现新的药物来阻断心脏病。