Senescence dysregulates of 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。失败 慢性炎症反应的解决是疾病进展的重要推动力 动脉硬化。解决是由专业的支持解决的调解人之间的关键平衡来调节的 (SPM)，如脂氧素和溶血素，以及促炎因子，如白三烯(LTS)和前列腺素 (PGS)。我们实验室和其他实验室之前的工作表明，SPM是在斑块中有缺陷地合成的 SPM的恢复可以防止小鼠动脉粥样硬化的进展。在我们对……的理解上仍然存在差距 A)是什么细胞过程扰乱了SPM的合成 SPM在动脉粥样硬化中的保护作用。因此， 斑块和b)与动脉粥样硬化相关的机制 这项建议的总体目标是理解 动脉粥样硬化中失调分解的新机制和利用新的SPM信号通路 走向一种新的治疗策略。细胞衰老是一种不可逆转的细胞周期停滞，导致高度 促炎表型称为衰老相关分泌表型(SASP)。突出 衰老细胞(SCs)的特征包括COX2和PGs水平升高和糖酵解增加。SCS 最近出现了斑块坏死的驱动因素，但其机制尚不清楚。我们的新作品 提示衰老损害了内源性的分辨率程序，关键的SPM可以限制SASP。 我们提出了一系列研究，以确定与衰老和受损相关的机制 分辨率(目标I)，髓系衰老细胞和斑块中SPM形成之间的联系(目标II)和 高胆固醇血症如何影响衰老和SPM合成的潜在机制(目标III)。这一链接 在失调的分解程序和衰老之间是一个全新的和未被探索的领域 研究可能揭示动脉粥样硬化的新治疗策略，这些策略是对那些 目前存在。

Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Failed resolution of a chronic inflammatory response is an important driving force in the progression of atherosclerosis. Resolution is mediated by the critical balance between specialized pro-resolving mediators (SPMs) such as lipoxins and resolvins and pro-inflammatory factors like leukotrienes (LTs) and prostaglandins (PGs). Previous work from our lab and others suggest that SPMs are defectively synthesized in plaques and that restoration of SPMs prevents atherosclerosis progression in mice. Gaps remain in our understanding as to a) what cellular processes derange the synthesis of SPMs in protective actions of SPMs in atherosclerosis. Therefore, the plaques and b) mechanisms associated with the overall objective of this proposal is to understand new mechanisms of dysregulated resolution in atherosclerosis and to harness new SPM signaling pathways towards a novel treatment strategy. Cellular senescence is an irreversible cell cycle arrest that leads to a highly pro-inflammatory phenotype called the senescence-associated secretory phenotype (SASP). Prominent features of senescent cells (SCs) include elevated levels of COX2 and PGs and heightened glycolysis. SCs recently emerged as a driver of plaque necrosis but mechanisms are poorly understood. Our new work suggests that senescence impairs endogenous resolution programs and that key SPMs can limit the SASP. We proposed a series of studies to identify the mechanisms associated with senescence and impaired resolution (Aim I), the link between myeloid senescent cells and SPM formation in plaques (Aim II) and mechanisms underlying how hypercholesterolemia impacts senescence and SPM synthesis (Aim III). The link between dysregulated resolution programs and senescence 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.