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）是工业化国家的主要死亡原因。过去十年的研究表明，慢性炎症反应的失败解决是动脉粥样硬化进展的重要驱动力。因此，两个关键的未回答的问题是：（a）在动脉粥样硬化中失调的解决方案的内源性机制是什么和（B）什么机制为基础的治疗策略可以设想启动解决时，它失败了。炎症的消退由专门的促消退介质（SPM）调节，所述促消退介质包括ω-6衍生的脂氧素和ω-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中失调的解决机制，并利用SPM信号通路实现新的治疗策略。5-脂氧合酶（5-LOX）是脂氧素和消退素生物合成的关键酶，在M？s，在动脉粥样硬化中大量存在。这个建议是为了测试的假设，SPM，通过5-LOX在M？s，限制动脉粥样硬化的进展并增强病变消退。目的1将探讨5-LOX在动脉粥样硬化中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将分别研究强调5-LOX如何保护动脉粥样硬化进展和消退的新的体内机制。目的2将验证假设，并探讨其中的机制，即5-LOX衍生的SPM消退素D1（RvD1）促进炎症消退和斑块稳定在动脉粥样硬化。使用Ldlr-/-小鼠喂养合成饮食诱导动脉粥样硬化，我将研究RvD1是否在两个临床相关模型中具有保护作用， 动脉粥样硬化;一种是模拟积极的降脂（子目标II-A），另一种是高脂血症是完整的（子目标II-B）。目的3将探索RvD1通过控制促炎介质（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，旨在为候选人提供成为心血管研究的独立科学家所需的技能的设置完成。在K99/指导阶段，申请人将继续获得分子、细胞和生物化学方法的专业知识，从机制的角度研究动脉粥样硬化的失调解决。由决议，CVD和转化科学领域的知名科学家/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.