Senescence dysregulates of inflammation-resolution programs in atherosclerosis

项目摘要 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。失败 慢性炎症反应的消退是动脉粥样硬化进展的重要驱动力。 解决是由专门的亲解决调解员（SPM）之间的关键平衡，如 脂氧素和消退素以及促炎因子如白三烯（LT）和前列腺素（PG）。 工作 SPMS 处理斑块和B）与保护性 SPM在动脉粥样硬化中的作用。因此，本行政补充文件的总体目标是， Masharh Lipscomb了解动脉粥样硬化中失调的新机制， 利用新的SPM信号通路实现新的治疗策略。细胞衰老是一种 不可逆的细胞周期停滞，导致高度促炎表型，称为衰老， 先前 来自我们实验室和其他实验室的研究表明，SPM在斑块中的合成是有缺陷的， 阻止小鼠动脉粥样硬化的进展。我们对以下问题的理解仍然存在差距：a）什么是细胞 扰乱SPM的合成， 相关分泌表型（SASP）。我们和其他人观察到，衰老细胞积累在 粥样硬化 清除 Masharh工作的一个主要目标是揭示为什么这些有害细胞不能轻易地 我们假设，SASP驱动增加的关键“不要'吃我”的信号，诱导 巨噬细胞以限制清除。这一行政补充将允许Masharh Lipscomb了解新的 技术，同时也提高了父母补助金的可交付成果的质量。

Project abstract 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). work SPMs processes plaques and b) mechanisms associated with the protective actions of SPMs in atherosclerosis. Therefore, the overall objective of this administrative supplement is for Masharh Lipscomb 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- Previous from our lab and others suggest that SPMs are defectively synthesized in plaques and that restoration of prevents atherosclerosis progression in mice. Gaps remain in our understanding as to a) what cellular derange the synthesis of SPMs in associated secretory phenotype (SASP). We and other observed that senescent cells accumulate in atherosclerosis cleared and a major goal of Masharh work is to uncover why these harmful cells cannot be readily and neutralized.We postulate that the SASP drives an increase in key “don't' eat me” signals that coax macrophages to limit clearance. This administrative supplement will allow Masharh Lipscomb to learn new techniques while also increasing the quality of the deliverables on the parent grant.