Necroptosis Impairs Inflammation-Resolution Programs in Atherosclerosis

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。研究 过去十年的研究表明，慢性炎症反应的未能解决是一个重要的驱动因素 在动脉粥样硬化进展过程中的力量。因此，两个关键的悬而未决的问题是：(A) 动脉粥样硬化中失调解决方案背后的内源性机制以及(B)什么 是否可以设想基于机制的治疗策略，以便在失败时启动解决方案？的决议案 炎症在一定程度上是由组成omega-6的专门的促分解介质(SPM)调节的 衍生的脂氧素和omega-3衍生的溶血素、保护素和松脂素。这项提案的总体目标是 是为了了解动脉粥样硬化中调节失调的分解机制，并利用SPM信号 通向新的治疗策略的途径。驱动失调解决方案的机制和过程 人们对动脉粥样硬化的课程很感兴趣。坏死性下垂是一种特殊的程序性细胞死亡形式，最近 成为动脉粥样硬化进展的驱动因素。我们的新工作表明，坏死性下垂本身会损害 内源性分解程序和关键的SPM可以限制坏死信号转导。我们提出了一系列 确定与坏死性下垂和分辨率受损相关的机制的研究(目标I)，这是 斑块中坏死性下垂与SPM形成之间的关系(AIM II)及其诱发SPM的机制 它们对巨噬细胞的抗坏死作用(目标III)。失调的解决方案之间的联系 而坏死性上睑下垂是一个全新的、未经探索的研究领域，可能会揭示新的治疗方法。 动脉粥样硬化的策略是对现有策略的补充。

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, in part, by specialized pro-resolving mediators (SPM) 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. Mechanisms and processes that drive dysregulated resolution programs in atherosclerosis are of interest. Necroptosis, a specific form of programmed cell death, has recently emerged as a driver of atherosclerosis progression. Our new work suggests that necroptosis itself impairs endogenous resolution programs and that key SPMs can limit necroptotic signaling. We proposed a series of studies to identify the mechanisms associated with necroptosis and impaired resolution (Aim I), the link between necroptosis and SPM formation in plaques (Aim II) and mechanisms underlying how SPMs evoke their anti-necroptotic actions on macrophages (Aim III). The link between dysregulated resolution programs and necroptosis is a completely new and unexplored area of research that may reveal new treatment strategies for atherosclerosis that are complementary to those that currently exist.