Specialized pro-resolving mediators in atherosclerosis

描述（由申请人提供）：动脉粥样硬化性心血管疾病（CVD）是工业化世界的主要死亡原因。过去十年的研究表明，慢性炎症反应的解决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)动脉粥样硬化中失调的解决方案的内源性机制是什么；(b)当解决方案失败时，可以设想基于何种机制的治疗策略来启动解决方案。炎症的消退是由专门的促消退介质（SPMs）调节的，这些介质包括omega-6衍生的脂毒素和omega-3衍生的溶解蛋白、保护蛋白和蛋白。本提案的总体目标是了解动脉粥样硬化中调节失调的机制，并利用SPM信号通路实现新的治疗策略。5-脂氧合酶（5- lox）是脂肪素和溶解素生物合成中的关键酶，在M？S，在动脉粥样硬化中大量存在。这一提议是为了验证SPM的假设，即通过M？S，限制动脉粥样硬化的进展并促进病变消退。目的1将探讨5-LOX在动脉粥样硬化中起保护作用的假设。利用嵌合Ldlr-/- 5-LOX-/-小鼠，亚靶I-A和B将分别研究新的体内机制，强调5-LOX如何保护动脉粥样硬化的进展和消退。目的2将验证这一假设，并研究其中的机制，即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。我将使用合成饲料喂养的Ldlr-/-小鼠诱导动脉粥样硬化，研究RvD1在两种临床相关的模型中是否具有保护作用

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.