Complement Protein C1q in Atherosclerosis

动脉粥样硬化中的补体蛋白 C1q

基本信息

项目摘要

PROJECT SUMMARY Complement Protein C1q in Atherosclerosis Atherosclerosis is a chronic inflammatory disorder which in early stages is characterized by the migration of modified lipoproteins and macrophages into the arterial intima and the formation and apoptosis of macrophage foam cells. In late stages of disease, inadequate/defective apoptotic foam cell removal by macrophages leads to their secondary necrosis and plaque formation. Damage to this plaque by pro-inflammatory cytokines, proteases and oxygen radicals can cause rupture and thrombus formation, and acute clinical complications such as myocardial infarction and ischemic stroke. Thus, inflammation, macrophages and vascular integrity are key in progression of this disease. Activation of complement has been shown to contribute to inflammation and exacerbate pathology. However, studies in mice deficient in the first protein in the classical complement pathway, C1q, suggest that this protein actually has a protective role in the early atherosclerotic lesion. Innate immune protein C1q is not only able to trigger the inflammatory complement cascade, but is also a pattern recognition receptor that opsonizes targets and directly interacts with phagocytes and other cells. Interaction activates responses including phagocytosis of targets such as apoptotic cells or damaged molecules, and modulation of cytokine and gene expression. Therefore, our central hypothesis is that complement-independent actions of C1q program protective, anti-atherosclerotic cellular responses in atherosclerosis. Our recent studies have demonstrated C1q modulation of macrophage inflammatory polarization in vitro and in vivo models of atherosclerosis and identified several molecular mechanisms involved. These studies provided preliminary data that C1q modulates vascular endothelial responses in atherosclerosis. In addition, data suggest that C1q increases levels of bioactive oxysterols 24- and 25- hydroxycholesterol by macrophages in response to hyperlipidemic conditions in vitro and in vivo. The goal of this project is to broaden our understanding of C1q molecular interactions beyond macrophages to the entire lesional environment. Specific aims are: 1: Investigate C1q modulation of vascular responses in atherosclerosis. We will test the hypothesis that C1q reduces monocyte chemotaxis and improves vascular integrity in atherosclerosis. This will be tested using primary human monocytes and vascular endothelial cells to perform chemotaxis, transendothelial migration and permeability assays. In addition, a comprehensive exploration of chemokines and adhesion molecules produced by macrophages and vascular endothelial cells in response to modified LDL in the presence or absence of C1q will be performed using human cells and in plasma harvested from C1q sufficient and deficient hyperlipidemic mice. Specific Aim 2: Investigate C1q modulation of lipid metabolism in atherosclerosis. These studies will test the hypothesis that C1q modulation of oxysterols is involved in macrophage foam cell survival and polarization. Oxysterol levels will be measured in vitro, in primary human macrophages, and in vivo in plasma from a mouse model of hyperlipidemia, using mass spectrometry. Survival and polarization assays will be performed in specific pathway-deficient macrophages to identify their relative importance in these biological responses. Overall, these studies aim to explore the dual role that C1q plays in atherosclerosis, and should assist in identifying novel molecular pathways for therapeutic targeting in this disease.
项目摘要 补体蛋白C1 q与动脉粥样硬化 动脉粥样硬化是一种慢性炎症性疾病,其在早期阶段的特征在于修饰的血管内皮细胞的迁移。 脂蛋白和巨噬细胞进入动脉内膜及巨噬泡沫细胞的形成和凋亡。月下旬 在疾病的不同阶段,巨噬细胞对凋亡泡沫细胞的去除不足/缺陷导致其继发性坏死, 斑块形成促炎细胞因子、蛋白酶和氧自由基对斑块的破坏可导致破裂 和血栓形成,以及急性临床并发症如心肌梗死和缺血性中风。因此,在本发明中, 炎症、巨噬细胞和血管完整性是这种疾病进展的关键。补体的激活具有 已被证明有助于炎症和恶化病理。然而,对缺乏第一种蛋白质的小鼠的研究 在经典补体途径中,C1 q,表明这种蛋白实际上在早期具有保护作用。 动脉粥样硬化病变先天免疫蛋白C1 q不仅能够触发炎症性补体级联反应,而且 也是一种模式识别受体,调理靶点并直接与吞噬细胞和其他细胞相互作用。相互作用 激活应答,包括对靶细胞如凋亡细胞或受损分子的吞噬作用,以及调节 细胞因子和基因表达。因此,我们的中心假设是C1 q程序的补体独立作用 动脉粥样硬化中的保护性抗动脉粥样硬化细胞反应。我们最近的研究表明C1 q 在动脉粥样硬化的体外和体内模型中调节巨噬细胞炎症极化,并鉴定了几种 涉及的分子机制。这些研究提供了C1 q调节血管内皮细胞的初步数据, 动脉粥样硬化的反应。此外,数据表明,C1 q增加了生物活性氧固醇24-和25-的水平。 在体外和体内,巨噬细胞对高脂血症条件的反应中产生羟基胆固醇。这个目标 该项目旨在将我们对C1 q分子相互作用的理解从巨噬细胞扩展到整个病变 环境具体目的如下:1.研究C1 q对动脉粥样硬化血管反应的调节作用。我们将测试 C1 q减少单核细胞趋化性并改善动脉粥样硬化血管完整性的假设。这将是 使用原代人单核细胞和血管内皮细胞进行趋化性、跨内皮迁移 和渗透性测定。此外,全面探索趋化因子和粘附分子产生的 巨噬细胞和血管内皮细胞在存在或不存在C1 q的情况下对修饰的LDL的反应将是 使用人细胞和从C1 q充足和缺乏的高血脂小鼠收获的血浆进行。具体 目的2:探讨C1 q对动脉粥样硬化脂质代谢的调节作用。这些研究将检验以下假设: 氧化固醇的C1 q调节参与巨噬细胞泡沫细胞存活和极化。氧固醇水平将 在体外、在原代人巨噬细胞中和在体内在来自高脂血症小鼠模型的血浆中测量,使用 质谱分析法来将在特定通路缺陷的巨噬细胞中进行存活和极化测定, 确定它们在这些生物反应中的相对重要性。总的来说,这些研究旨在探索C1 q的双重作用, 在动脉粥样硬化中起作用,并应有助于确定这种疾病的治疗靶向的新分子途径。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Complement Protein C1q Enhances Macrophage Foam Cell Survival and Efferocytosis.
Transcriptome data and gene ontology analysis in human macrophages ingesting modified lipoproteins in the presence or absence of complement protein C1q.
在补体蛋白 C1q 存在或不存在的情况下摄取修饰脂蛋白的人巨噬细胞的转录组数据和基因本体分析。
  • DOI:
    10.1016/j.dib.2016.09.008
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    1.2
  • 作者:
    Ho,Minh-Minh;Fraser,DeborahA
  • 通讯作者:
    Fraser,DeborahA
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Deborah Ann Fraser其他文献

Deborah Ann Fraser的其他文献

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{{ truncateString('Deborah Ann Fraser', 18)}}的其他基金

Complement Protein C1q Regulation of Macrophage Metabolic Pathways
补体蛋白 C1q 对巨噬细胞代谢途径的调节
  • 批准号:
    10629550
  • 财政年份:
    2023
  • 资助金额:
    $ 11.06万
  • 项目类别:
Complement and Macrophage Polarization in Atherosclerosis
动脉粥样硬化中的补体和巨噬细胞极化
  • 批准号:
    8741850
  • 财政年份:
    2014
  • 资助金额:
    $ 11.06万
  • 项目类别:
Complement and Macrophage Polarization in Atherosclerosis
动脉粥样硬化中的补体和巨噬细胞极化
  • 批准号:
    9274342
  • 财政年份:
    2014
  • 资助金额:
    $ 11.06万
  • 项目类别:
Complement Protein C1q in Atherosclerosis
动脉粥样硬化中的补体蛋白 C1q
  • 批准号:
    10117075
  • 财政年份:
    2014
  • 资助金额:
    $ 11.06万
  • 项目类别:
Complement Protein C1q in Atherosclerosis
动脉粥样硬化中的补体蛋白 C1q
  • 批准号:
    9883812
  • 财政年份:
    2014
  • 资助金额:
    $ 11.06万
  • 项目类别:

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