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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

基本信息

批准号：
10629550
负责人：
Deborah Ann Fraser
金额：
$ 14.28万
依托单位：
CALIFORNIA STATE UNIVERSITY LONG BEACH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629550
关键词：
Anti-Inflammatory Agents Apoptosis Apoptotic Arterial Fatty Streak Atherosclerosis Autoimmune Diseases Autophagocytosis Binding Biological Biological Assay Bone Marrow C1q deficiency Cardiovascular Diseases Cell Survival Cells Cholesterol Cholesterol Homeostasis Chronic Clinical Complement Complement 1q Complement Activation Cytokine Signaling Dangerousness Data Desmosterol Development Disease Disease Progression Environment Enzymes Excision Foam Cells Gene Expression Glucose Glycolysis Goals Homeostasis Human Immune Immune response In Vitro Inflammation Inflammatory Ingestion Investigation Ischemic Stroke Lipids Lipoproteins Liver X Receptor Macrophage Mass Spectrum Analysis Measures Metabolic Metabolic Pathway Microglia Mitochondria Molecular Molecular Mechanisms of Action Mus Myocardial Infarction Myocardial Ischemia Necrosis Normal tissue morphology Nuclear Outcome Pathology Pathway interactions Peptide Hydrolases Perception Phagocytes Phagocytosis Phenotype Play Production Proteins Public Health Reactive Oxygen Species Regulation Reporting Respiration Role Signal Transduction Sterols Superoxides Testing Time Tissues Work autocrine complement pathway cytokine improved in vivo Model inhibitor knock-down lipid metabolism lipidomics migration mitochondrial autophagy mitochondrial metabolism monocyte new therapeutic target novel oxidized low density lipoprotein paracrine pathogen prevent programs response therapeutic development therapeutic target uptake

项目摘要

Complement Protein C1q Regulation of Macrophage Metabolic Pathways PROJECT SUMMARY Atherosclerosis is a chronic inflammatory disorder which in early stages is characterized by the migration of macrophages and modified lipoproteins into the arterial walls, leading to the formation and apoptosis of macrophage foam cells. In late stages of disease, insufficient apoptotic foam cell removal by macrophages leads to their secondary necrosis and plaque development. Plaque damage by pro-inflammatory cytokines, proteases and oxygen radicals can lead to clinical complications such as myocardial infarction and ischemic stroke. Thus, macrophage foam cell survival, cholesterol removal, and inflammation are key factors in progression of this disease. Complement pathway activation by innate immune protein C1q has been shown to promote disease progression. However, studies in C1q-deficient mice suggest a protective role for C1q in the early atherosclerotic lesion. In addition to complement activation, C1q can directly opsonize targets and interacts with phagocytes leading to increased phagocytic responses and reduced inflammatory cytokine signaling. Macrophages can synthesize C1q and therefore C1q may be localized in macrophage-rich tissues, such as the early atherosclerotic lesion, in the absence of other complement components needed for complement activation. Therefore, our central hypothesis is that complement-independent actions of C1q program protective, anti-atherosclerotic macrophage responses in atherosclerosis. Recent studies have identified a number of potentially beneficial mechanisms of C1q on macrophage survival, efferocytosis, cholesterol metabolism, and inflammatory polarization in vitro and in vivo models of atherosclerosis. The goal of this project is to investigate pathways and biological relevance of C1q modulation of cholesterol metabolism, and to determine for the first time if there is a role for C1q in mitochondrial metabolism in macrophage foam cells. Specific aims are: 1: Investigate C1q modulation of lipid metabolism in macrophages and microglia. We will test the hypothesis that C1q modulation of LXR-activating lipids 24-OHC, 25-OHC, and desmosterol are involved in macrophage foam cell survival, efferocytosis and polarization. Lipidomic analysis will be performed in primary human M0, M1, or M2 polarized macrophage foam cells and murine microglia ±C1q. Survival, efferocytosis, and polarization assays will be performed in specific pathway-deficient or knocked-down macrophages to identify their relative importance in these biological responses. Specific Aim 2: Investigate C1q modulation of macrophage metabolic programming. We will test the hypothesis that C1q modulation of mitochondrial metabolism and autophagy are involved in macrophage foam cell survival, efferocytosis, and polarization. Changes to mitochondrial respiration, glycolysis and superoxide production will be measured in human monocyte-derived macrophages during ingestion of oxLDL ±C1q. Similar studies will be performed in murine bone marrow-derived macrophages from wild-type or C1q-deficient mice to investigate autocrine vs. paracrine actions of C1q. Assays will be repeated in macrophages ingesting oxLDL ±C1q in the presence of autophagy (or other metabolic pathway) inhibitors, or cultured in high glucose environment to identify involvement of metabolic pathways 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.

补体C1 q蛋白对巨噬细胞代谢途径的调控项目摘要动脉粥样硬化是一种慢性炎症性疾病，其早期特征是巨噬细胞的迁移和修饰的脂蛋白进入动脉壁，导致巨噬细胞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清除不足，导致其继发性坏死和斑块发展由促炎性细胞因子、蛋白酶和氧自由基引起的斑块损伤可导致临床并发症如心肌梗死和缺血性中风。因此，巨噬细胞泡沫细胞存活，胆固醇切除和炎症是这种疾病进展的关键因素。先天性补体途径激活免疫蛋白C1 q已显示促进疾病进展。然而，对C1 q缺陷小鼠的研究表明， C1 q在早期动脉粥样硬化病变中的保护作用。除了补体激活，C1 q可以直接调理靶向并与吞噬细胞相互作用，导致吞噬反应增加和炎性细胞因子减少信号巨噬细胞可以合成C1 q，因此C1 q可能定位于富含巨噬细胞的组织，如在缺乏补体激活所需的其他补体成分的情况下，早期动脉粥样硬化病变。因此，我们认为，我们的中心假设是C1 q程序的补体非依赖性作用保护、抗动脉粥样硬化动脉粥样硬化中的巨噬细胞反应。最近的研究已经确定了一些潜在的有益机制 C1 q对巨噬细胞存活、巨噬细胞增多、胆固醇代谢和体内外炎症极化的影响动脉粥样硬化模型。本项目的目标是研究C1 q调节的途径和生物学相关性，胆固醇代谢，并首次确定C1 q在线粒体代谢中的作用，巨噬泡沫细胞具体目的是：1.研究巨噬细胞中C1 q对脂质代谢的调节，小胶质细胞我们将检验C1 q调节LXR激活脂质24-OHC、25-OHC和桥甾醇的假设，参与巨噬细胞泡沫细胞存活、巨噬细胞增多和极化。脂质组学分析将在原代人M0、M1或M2极化巨噬泡沫细胞和鼠小胶质细胞± C1 q。存活率，红细胞增多症，将在特定通路缺陷或敲低的巨噬细胞中进行极化测定，以鉴定它们的相对活性。这些生物反应的重要性。具体目的2：研究巨噬细胞代谢的C1 q调节编程.我们将检验C1 q调节线粒体代谢和自噬的假设在巨噬细胞泡沫细胞存活、巨噬细胞增多和极化中的作用。线粒体呼吸、糖酵解和在摄取oxLDL ± C1 q期间，在人单核细胞衍生的巨噬细胞中测量超氧化物的产生。将在野生型或C1 q缺陷小鼠的小鼠骨髓源性巨噬细胞中进行类似的研究，研究C1 q自分泌与旁分泌作用。将在巨噬细胞中重复测定巨噬细胞oxLDL ± C1 q，存在自噬（或其他代谢途径）抑制剂，或在高葡萄糖环境中培养以鉴定代谢途径参与这些生物反应。总的来说，这些研究旨在探讨 C1 q在动脉粥样硬化中发挥作用，并应有助于确定新的分子通路的治疗靶向。