Senescence dysregulates of inflammation-resolution programs in atherosclerosis

动脉粥样硬化炎症消退程序的衰老失调

• 批准号: 10631070
• 负责人: Gabrielle Fredman
• 金额: $ 61.78万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631070
• 关键词: Acetylation; Acute; Area; Arterial Fatty Streak; Atherosclerosis; Blocking Antibodies; Cancer Patient; Cardiovascular Diseases; Cause of Death; Cell Aging; Cell Cycle Arrest; Cell physiology; Cells; Chronic; Data; Diet; Dinoprostone; Eating; Enzymes; Equilibrium; Etiology; Event; Exhibits; Glycolysis; Human; Impairment; In Vitro; Industrialization; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Leukotrienes; Link; Lipoxins; Mediating; Mediator; Modeling; Mus; Myelogenous; Myeloid Cells; Necrosis; PTGS2 gene; Phenotype; Process; Production; Prostaglandins; Radiation; Regulation; Research; Resolution; Series; Signal Pathway; Signal Transduction; Surface; Testing; Work; cardiovascular disorder risk; driving force; hypercholesterolemia; improved; in vivo; insight; mouse model; novel; novel therapeutic intervention; prevent; programs; public health priorities; restoration; restraint; senescence; tissue injury; tissue repair; treatment strategy

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.

动脉粥样硬化心血管疾病（CVD）是工业化世界中死亡的主要原因。失败的 慢性炎症反应的分辨率是进展的重要驱动力 动脉粥样硬化。分辨率是由专业的促进调解人之间的关键平衡来介导的 （SPMS），例如脂毒素和溶质和促炎性因素，例如白细胞（LTS）和前列腺素 （PGS）。我们实验室和其他人的先前工作表明，SPM是在斑块中缺陷合成的 SPM的恢复可防止小鼠动脉粥样硬化的进展。差距在我们的理解中仍然存在 a）哪种细胞过程使SPMS合成在哪种细胞过程中 SPM在动脉粥样硬化中的保护作用。因此， 斑块和b）与 该提议的总体目的是了解 动脉粥样硬化和利用新的SPM信号传导途径的分辨率失调的新机制 采取新颖的治疗策略。细胞衰老是一种不可逆的细胞周期停滞，导致高度 促炎的表型称为衰老相关的分泌表型（SASP）。著名的 衰老细胞（SC）的特征包括COX2和PG的水平升高以及糖酵解的增强。 SCS 最近出现成为斑块坏死的驱动力，但机制知之甚少。我们的新作品 表明衰老会损害内源性分辨率计划，而关键SPM可以限制SASP。 我们提出了一系列研究，以识别与衰老相关的机制和受损 分辨率（AIM I），斑块中的髓样衰变细胞与SPM形成之间的联系（AIM II）和 高胆固醇血症如何影响衰老和SPM合成的机制（AIM III）。链接 在失调的分辨率计划和衰老之间是一个全新且未开发的领域 研究可能揭示了针对动脉粥样硬化的新治疗策略，这与那些 目前存在。