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，慢性炎症反应的失败是动脉粥样硬化进展的重要驱动力。因此，两个关键的悬而未决的问题是：(A)动脉粥样硬化失调解决方案背后的内源性机制是什么；(B)当动脉粥样硬化失败时，可以设想什么基于机制的治疗策略来启动解决方案。炎症的分解由专门的促分解介体(SPM)调节，SPM由omega-6衍生的脂氧素和omega-3衍生的分解素、保护素和松脂组成。这项建议的总体目标是了解动脉粥样硬化中失衡的分解机制，并利用SPM信号通路走向新的治疗策略。5-脂氧合酶(5-LOX)是脂氧素和解脂素生物合成的关键酶，在动脉粥样硬化中含量丰富的M？S体内有表达。本研究旨在验证M？S患者SPM通过5-LOX限制动脉粥样硬化进展和促进病变消退的假说。目的1探讨5-LOX对动脉粥样硬化具有保护作用的假说。利用嵌合的Ldlr-/--5-LOX-/-小鼠，Sub Aim I-A和B将研究新的体内机制，强调5-LOX如何分别保护动脉粥样硬化的进展和消退。目的2验证这一假说，并探讨其机制，即5-LOX来源的SPM解析素D1(RvD1)可促进动脉粥样硬化中炎症的消退和斑块的稳定。用人工合成饲料喂养的Ldlr-/-小鼠诱导动脉粥样硬化，我将研究Rvd1在两个临床相关的 动脉粥样硬化；模拟积极降脂(亚目的II-A)和高脂血症正常的亚目的(亚目的II-B)。目的3探讨Rvd1通过控制促炎症介质(如白三烯B4)和促分解介质(如脂氧素A4)之间的平衡来调节5-LOX的假说，这是一个关键的分解机制。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领域独立科学家所需的技能。在获奖的K99/指导阶段，申请者将继续获得分子、细胞和生化方法的专业知识，从机械论的角度研究动脉粥样硬化中的失调分解。一个由解决方案、心血管疾病和翻译科学领域的知名科学家/导师组成的咨询委员会将在获奖期内指导候选人向科学独立过渡。

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.