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

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）：动脉粥样硬化性心血管疾病（CVD）是工业化国家的首要死因。过去十年的研究表明，慢性炎症反应未能解决是动脉粥样硬化进展的重要驱动力。因此，两个尚未解答的关键问题是：(a) 动脉粥样硬化失调解决方案背后的内源机制是什么；(b) 可以设想哪些基于机制的治疗策略来在解决方案失败时启动解决方案。炎症的消退受到专门的促消退介质 (SPM) 的调节，这些介质包括 omega-6 衍生的脂氧素和 omega-3 衍生的消退素、保护素和 maresins。该提案的总体目标是了解动脉粥样硬化失调消退的机制，并利用 SPM 信号通路制定新的治疗策略。 5-脂氧合酶 (5-LOX) 是脂氧素和分解素生物合成中的关键酶，在 M?s 中表达，M?s 在动脉粥样硬化中含量丰富。该提案旨在检验以下假设：SPM 通过 M 中的 5-LOX 限制动脉粥样硬化的进展并增强动脉粥样硬化的病变消退。目标 1 将探讨 5-LOX 对动脉粥样硬化具有保护作用的假设。使用嵌合 Ldlr-/--5-LOX-/- 小鼠，子目标 I-A 和 B 将研究新的体内机制，强调 5-LOX 如何分别防止动脉粥样硬化进展和消退。目标 2 将检验以下假设并研究其中的机制：5-LOX 衍生的 SPM resolvin D1 (RvD1) 促进动脉粥样硬化中的炎症消退和斑块稳定。使用合成饮食喂养的 Ldlr-/- 小鼠来诱导动脉粥样硬化，我将研究 RvD1 在两个临床相关模型中是否具有保护作用 动脉粥样硬化;一种模拟积极降脂（子目标 II-A），另一种则保持高脂血症完整（子目标 II-B）。目标 3 将探讨 RvD1 通过控制促炎症介质（例如白三烯 B4）和促消退介质（例如脂氧素 A4）之间的平衡来调节 5-LOX 的假设，这是消退的关键机制。这项研究将在一个全面的职业发展计划的背景下完成，该计划旨在为候选人提供成为心血管研究独立科学家所需的技能。在该奖项的 K99/指导阶段，申请人将继续获得分子、细胞和生化方法的专业知识，从机制的角度研究动脉粥样硬化的失调解决方案。由分辨率、心血管疾病和转化科学领域知名科学家/导师组成的咨询委员会将指导候选人在获奖期间过渡到科学独立。