Specialized pro-resolving mediators in atherosclerosis

动脉粥样硬化的专门促解决介质

• 批准号: 8566813
• 负责人: Gabrielle Fredman
• 金额: $ 10.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566813
• 关键词: Address; Advisory Committees; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Apoptosis; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Area; Aspirin; Atherosclerosis; Award; Biochemical; Bone Marrow; CD59 Antigen; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Chronic; Collaborations; Collagen; Data; Disease model; Eicosanoids; Enhancing Lesion; Enzymes; Equilibrium; Extracellular Matrix; Generations; Genes; Hyperlipidemia; Inflammation; Inflammatory; Inflammatory Response; Lasers; Learning; Lesion; Leukotriene B4; Leukotrienes; Lipids; Lipoxins; MAPK14 gene; Mediator of activation protein; Mentors; Microscopy; Modeling; Molecular; Molecular Profiling; Mus; Necrosis; Nuclear; Omega-3 Fatty Acids; Peritonitis; Phase; Phenotype; Phosphorylation; Research; Resolution; Role; Scientist; Serine; Signal Pathway; Signal Transduction; Simulate; Site; Solid; Synthetic Diet; Techniques; Testing; Translational Research; Zymosan; base; career development; clinically relevant; cohort; cytokine; design; driving force; feeding; in vivo; lipoxin A4; macrophage; mutant; novel; novel therapeutic intervention; programs; research study; skills; treatment strategy; Address; Advisory Committees; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Apoptosis; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Area; Aspirin; Atherosclerosis; Award; Biochemical; Bone Marrow; CD59 Antigen; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Chronic; Collaborations; Collagen; Data; Disease model; Eicosanoids; Enhancing Lesion; Enzymes; Equilibrium; Extracellular Matrix; Generations; Genes; Hyperlipidemia; Inflammation; Inflammatory; Inflammatory Response; Lasers; Learning; Lesion; Leukotriene B4; Leukotrienes; Lipids; Lipoxins; MAPK14 gene; Mediator of activation protein; Mentors; Microscopy; Modeling; Molecular; Molecular Profiling; Mus; Necrosis; Nuclear; Omega-3 Fatty Acids; Peritonitis; Phase; Phenotype; Phosphorylation; Research; Resolution; Role; Scientist; Serine; Signal Pathway; Signal Transduction; Simulate; Site; Solid; Synthetic Diet; Techniques; Testing; Translational Research; Zymosan; base; career development; clinically relevant; cohort; cytokine; design; driving force; feeding; in vivo; lipoxin A4; macrophage; mutant; novel; novel therapeutic intervention; programs; research study; skills; treatment strategy

DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Studies over the last decade suggest that failed resolution of a chronic inflammatory response is an important driving force in the progression of atherosclerosis. Accordingly, two critical unanswered questions are: (a) what are the endogenous mechanisms underlying dysregulated resolution programs in atherosclerosis and (b) what mechanism-based treatment strategies can be conceived to initiate resolution when it fails. The resolution of inflammation is regulated by specialized pro-resolving mediators (SPMs) that comprise omega-6 derived lipoxins and omega-3 derived resolvins, protectins and maresins. The overall objective of this proposal is to understand the mechanisms of dysregulated resolution in atherosclerosis and to harness SPM signaling pathways towards a novel treatment strategy. A critical enzyme in the biosynthesis of lipoxins and resolvins, 5- lipoxygenase (5-LOX) is expressed in M?s, which are abundant in atherosclerosis. This proposal is to test the hypothesis that SPM, via 5-LOX in M?s, limit progression and enhance lesion regression in atherosclerosis. Aim 1 will explore the hypothesis 5-LOX is protective in atherosclerosis. Using chimeric Ldlr-/--5-LOX-/- mice, Sub aim I-A and B will investigate new in vivo mechanisms that underscore how 5-LOX is protective against atherosclerosis progression and regression respectively. Aim 2 will test the hypothesis, and investigate the mechanisms therein, that the 5-LOX-derived SPM resolvin D1 (RvD1) promotes inflammation resolution and plaque stabilization in atherosclerosis. Using Ldlr-/- mice fed on a synthetic diet to induce atherosclerosis, I will investigate whether RvD1 is protective in two clinically relevant models of atherosclerosis; one that simulates aggressive lipid lowering (Sub aim II-A) and one where hyperlipidemia is intact (Sub aim II-B). Aim 3 will explore the hypothesis the RvD1 regulates 5-LOX by controlling the balance between pro-inflammatory (e.g. leukotriene B4) and pro-resolving mediators (e.g. lipoxin A4), a key mechanism of resolution. This research will be accomplished in the setting of a comprehensive career development program designed to provide the candidate with the skills needed to become an independent scientist in cardiovascular research. During the K99/Mentored phase of the award the applicant will continue to gain expertise molecular, cellular and biochemical approaches to study the dysregulated resolution in atherosclerosis from a mechanistic standpoint. An advisory committee of established scientists/mentors in the fields of resolution, CVD and translational science will guide the candidate in her transition to scientific independence over the course of the award period.

描述（由申请人提供）：动脉粥样硬化心血管疾病（CVD）是工业化世界中死亡的主要原因。在过去的十年中，研究表明，慢性炎症反应的分辨率失败是动脉粥样硬化进展的重要驱动力。因此，两个关键的未解决的问题是：（a）动脉粥样硬化中的分辨率失调计划的内源性机制是什么，（b）（b）在失败时可以构想哪些基于机制的治疗策略来启动解决方案。炎症的分辨率由构成Omega-6衍生的脂毒素和omega-3衍生的Resolvins，Protectins和Maresins的专门促进介质（SPM）调节。该提案的总体目的是了解动脉粥样硬化中分辨率失调的机制，并利用SPM信号传导途径达到新的治疗策略。脂毒素和溶质素的生物合成中的关键酶，5-脂氧合酶（5-lox）在M？s中表达，在动脉粥样硬化中含量丰富。该建议是测试以下假设：SPM通过M se的5-lox限制进展并增强动脉粥样硬化的病变消退。 AIM 1将探索假设5-Lox在动脉粥样硬化中具有保护性。使用嵌合LDLR - / - 5-lox - / - 小鼠，Sub Aim I-A和B将研究新的体内机制，这些机制强调了5-LOX分别针对动脉粥样硬化的进展和回归。 AIM 2将检验假设，并研究其中的机制，即5-lox衍生的SPM Resolvin D1（RVD1）促进了动脉粥样硬化中的炎症分辨率和斑块稳定。使用液化脂蛋白 - / - 小鼠以合成饮食诱导动脉粥样硬化，我将研究RVD1在两个临床相关的模型中是否具有保护性 动脉粥样硬化；一种模拟攻击性脂质降低（sub aim ii-a），而高脂血症完好无损的一种（sub aim ii-b）。 AIM 3将探讨RVD1通过控制促炎（例如白细胞B4）和促分解介体（例如Lipoxin A4）之间的平衡来调节5-LOX的假设。这项研究将在综合职业发展计划的设置中完成，旨在为候选人提供成为心血管研究中独立科学家所需的技能。在奖励的K99/指导阶段，申请人将继续获得专业知识的分子，细胞和生化方法，以研究动脉粥样硬化的分辨率从机械的角度研究动脉粥样硬化的分辨率。在决议，CVD和转化科学领域成熟的科学家/导师的咨询委员会将指导候选人在整个奖项期间过渡到科学独立性。