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.
项目总结 补体蛋白C1q与动脉粥样硬化 动脉粥样硬化是一种慢性炎症性疾病,早期的特点是变性血管的迁移 脂蛋白和巨噬细胞进入动脉内膜及巨噬细胞泡沫细胞的形成和凋亡。在晚些时候 疾病阶段,巨噬细胞清除不充分/缺陷的凋亡性泡沫细胞会导致继发性坏死和 斑块形成。促炎症细胞因子、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, 炎症、巨噬细胞和血管完整性是该病进展的关键。激活补体HAS 已被证明会导致炎症并加剧病理。然而,对缺乏第一种蛋白质的小鼠的研究 在经典的补体途径中,C1q表明这种蛋白质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C1q不仅能够触发炎性补体级联反应,而且 也是一种模式识别受体,能调理靶细胞并直接与吞噬细胞和其他细胞相互作用。相互作用 激活反应,包括吞噬靶细胞,如凋亡细胞或受损分子,并调节 细胞因子和基因表达。因此,我们的中心假设是C1q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。我们最近的研究证明了C1q 巨噬细胞炎症极化在动脉粥样硬化体外和体内模型中的调节及鉴定 涉及的分子机制。这些研究提供了C1q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,C1q会增加生物活性氧固醇24-和25-的水平。 体外和体内巨噬细胞对高脂状态下的羟基胆固醇反应。这样做的目的是 项目是将我们对C1q分子相互作用的理解从巨噬细胞扩大到整个皮损 环境。具体目标为:1:研究动脉粥样硬化中血管反应的C1q调节。我们将测试 C1q在动脉粥样硬化中减少单核细胞趋化和改善血管完整性的假说。这将是 使用原代人类单核细胞和血管内皮细胞进行测试,以执行趋化、跨内皮迁移 和通透性分析。此外,对趋化因子和黏附分子的全面探索 巨噬细胞和血管内皮细胞对修饰的低密度脂蛋白是否存在C1q的反应 使用人类细胞和从C1q充足和缺乏的高脂血症小鼠采集的血浆中进行。特定的 目的2:探讨动脉粥样硬化中C1q对脂代谢的调节作用。这些研究将检验这一假设 氧化甾醇的C1q调节参与巨噬泡沫细胞的存活和极化。氧固醇水平将会是 在体外、原代人类巨噬细胞和高脂血症小鼠模型的体内血浆中进行测量,使用 质谱学。将对特定途径缺陷的巨噬细胞进行存活和极化分析,以 确定它们在这些生物反应中的相对重要性。总体而言,这些研究旨在探索C1q的双重角色 在动脉粥样硬化中发挥作用,应该有助于确定治疗这种疾病的新的分子途径。

项目成果

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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 Protein C1q in Atherosclerosis
动脉粥样硬化中的补体蛋白 C1q
  • 批准号:
    10359780
  • 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:
    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:

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