Necroptosis Impairs Inflammation-Resolution Programs in Atherosclerosis

坏死性凋亡损害动脉粥样硬化的炎症消退程序

基本信息

批准号：
10349539
负责人：
Gabrielle Fredman
金额：
$ 42.76万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349539
关键词：
Acute Affect Anabolism Anti-CD47 Apoptosis Arachidonate 5-Lipoxygenase Area Arterial Fatty Streak Atherosclerosis CD47 gene CD59 Antigen Cardiovascular Diseases Cause of Death Cell Death Cells Chronic Complex Data Eating Electron Transport Complex III Enzymes Equilibrium Event Generations Homeostasis Human Image Impairment Industrialization Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Lesion Leukotrienes Link Lipoxins Measures Mediating Mediator of activation protein Membrane Methods Microscope Mus Necrosis Omega-3 Fatty Acids Omega-6 Fatty Acids Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Process Proteins Regulation Research Resolution Role Rupture Series Short Interspersed Nucleotide Elements Signal Pathway Signal Transduction System Testing Thinness Tissues Work base driving force in vivo insight interest knock-down macrophage novel prevent programs public health priorities receptor release factor repaired response tissue injury tissue repair treatment strategy

项目摘要

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.

动脉粥样硬化性心血管疾病（CVD）是工业化国家的首要死因。研究过去十年表明，慢性炎症反应未能解决是一个重要的驱动因素动脉粥样硬化进展的力量。因此，有两个尚未解答的关键问题是：(a) 什么是动脉粥样硬化解决方案失调的内源性机制以及 (b) 什么可以设想基于机制的治疗策略在失败时启动解决方案吗？分辨率为炎症部分由包含 omega-6 的专门促消退介质 (SPM) 调节衍生的脂氧素和 omega-3 衍生的分解素、保护素和 maresins。本提案的总体目标旨在了解动脉粥样硬化解决失调的机制并利用 SPM 信号传导通往新治疗策略的途径。驱动失调解决方案的机制和流程动脉粥样硬化的项目很有趣。坏死性凋亡是程序性细胞死亡的一种特殊形式，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凋亡本身会损害内源性解析程序和关键 SPM 可以限制坏死性凋亡信号传导。我们提出了一系列研究确定与坏死性凋亡和分辨率受损相关的机制（目标 I），链接坏死性凋亡和斑块中 SPM 形成之间的关系（目标 II）以及 SPM 诱发的机制它们对巨噬细胞的抗坏死性凋亡作用（目标 III）。失调解决方案之间的联系坏死性凋亡是一个全新的、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。