权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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）是工业化国家的主要死亡原因。研究在过去的十年中表明，慢性炎症反应的失败解决是一个重要的驱动力，在动脉粥样硬化的进展中的力量。因此，两个关键的未回答的问题是：（a）什么是动脉粥样硬化中失调的消退程序背后的内源性机制和（B）什么机制为基础的治疗策略可以设想启动解决时，它失败了？的分辨率炎症部分地由包括ω-6的特化促消退介质（SPM）调节衍生的脂氧素和ω-3衍生的消退素、保护素和maresins。本提案的总体目标是是了解动脉粥样硬化中失调的解决机制，通往新型治疗策略的途径。驱动失调解决的机制和过程动脉粥样硬化的研究项目是很有意义的。坏死性凋亡是程序性细胞死亡的一种特殊形式，成为动脉粥样硬化进展的驱动因素。我们的新研究表明坏死性凋亡本身内源性解决方案和关键SPM可以限制坏死性凋亡信号。我们提出了一系列研究，以确定与坏死性凋亡和受损的解决机制（目的I），链接斑块中坏死性凋亡和SPM形成之间的关系（目的II）以及SPM如何引起它们对巨噬细胞的抗坏死性凋亡作用（Aim III）。失调的解决方案之间的联系而坏死性凋亡是一个全新的、未经探索的研究领域，动脉粥样硬化的治疗策略是对现有治疗策略的补充。