Macrophage Lipid Homeostasis and Inflammatory Signaling

巨噬细胞脂质稳态和炎症信号传导

基本信息

批准号：
10161852
负责人：
STEVEN J BENSINGER
金额：
$ 45.88万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161852
关键词：
Address Affect Anti-Inflammatory Agents Arterial Fatty Streak Atherosclerosis Attenuated Binding Biochemical Cardiovascular Diseases Cell membrane Cell physiology Cells Cellular Immunity Cholesterol Cholesterol Homeostasis Cytosol Data Dendritic Cells Development Disease Dyslipidemias Ensure Event Genes Genetic Models Goals Gram-Positive Bacteria Health Homeostasis Image Immune Immunity Immunologic Receptors Infiltration Inflammation Inflammatory Inflammatory Response Interferon-beta Interferons Isotope Labeling Isotopes Laboratories Link Lipids Mass Spectrum Analysis Membrane Metabolic Mitochondria Modeling Molecular Movement Mus Mutation Pathogenesis Pathologic Pathway interactions Physiology Positioning Attribute Production Proteins Reagent Regulation Role Shotguns Signal Pathway Signal Transduction Sterility Stimulator of Interferon Genes TLR2 gene TLR3 gene Techniques Technology Testing Therapeutic Intervention Toll-like receptors Tracer Work advanced analytics atherogenesis base chemoproteomics cholesterol trafficking cytokine design expectation fatty acid biosynthesis human disease immune function lipid metabolism lipid transport lipidome lipidomics loss of function macrophage mouse model novel novel strategies response trafficking viral RNA

项目摘要

Project 2: Macrophage Lipid Homeostasis and Inflammatory Signaling ABSTRACT/SUMMARY The objective of Project 2 of this PPG is to understand how cellular lipid composition and lipid trafficking influence the inflammatory function of macrophages. Although perturbations in lipid homeostasis are recognized to be associated with inflammation in a number of human diseases, our understanding of “how” and “why” remains limited. Recent work has revealed that pro-inflammatory signals reprogram the lipid metabolic state of macrophages. It has also become clear that perturbations in lipid homeostasis can be sensed by the inflammatory machinery of macrophages so as to induce and to regulate inflammatory responses. Thus, lipid homeostasis and inflammation are interrelated, and perturbations in one affect the other. In this project, our PPG team will combine advanced analytical mass spectrometry–based approaches with genetic models of inflammation, with the goal of defining mechanisms by which inflammation drives reprogramming of the lipidome (and vice versa). We will assess the consequences of changing the subcellular levels of lipids on inflammatory signaling. Specific Aim 1 is to apply advanced analytic techniques to determine how pro- and anti-inflammatory signals change the subcellular lipidome in macrophages. We will use mass spectrometry approaches, including shotgun lipidomics, NanoSIMS imaging, and isotope labeling, to understanding how pro- and anti-inflammatory signals influence lipid localization and trafficking in macrophages. Specific Aim 2 is to determine the mechanisms by which alterations in cholesterol homeostasis potentiate the STING signaling pathway. We will pursue our discovery that perturbations in de novo cholesterol synthesis change type I IFN inflammatory responses via STING. Using a combination of biochemical approaches, confocal and NanoSIMS imaging, and chemoproteomics, we will test the hypothesis that cholesterol regulates STING function through direct binding. We will also test whether disease-associated mutations in STING abrogate the regulatory impact of cholesterol. Specific Aim 3 is to determine the importance of the STING signaling pathway on the development of dyslipidemia, inflammation, and atherogenesis in mice. Type I IFNs have been shown to influence the pathogenesis of atherosclerosis, but the molecular pathways underlying this sterile inflammatory response have not been elucidated. We will test the hypothesis that the cGAS/STING inflammatory axis is required to generate type I IFN in the setting of dyslipidemia and atherosclerosis. These studies will define the influence of the STING pathway on dyslipidemia, inflammation, immune cell infiltration, and atheroma development. It is our expectation that our proposed studies will define, at a molecular level, why dysregulation of macrophage lipid homeostasis drives inflammation, and how inflammation influences macrophage cholesterol metabolism in cardiovascular disease. Our PPG team is excited by our hypotheses, and we are positioned, with all of the experimental approaches, reagents, and expert collaborators, to make rapid progress.

项目2：巨噬细胞脂质稳态和炎症信号传导摘要/摘要 PPG项目2的目的是了解细胞脂质成分和脂质运输方式影响巨噬细胞的炎症功能。我们公认与许多人类疾病中的炎症有关，我们对“如何”的理解 “为什么”仍然有限。巨噬细胞的代谢状态也很明显脂质稳态的扰动通过巨噬细胞的炎症机制感应到屁股，以诱导和调节炎症响应。在这个项目中，我们的PPG团队将结合先进的分析质量特别质量特别的方法和炎症的遗传模型，目的是防御炎症驱动的机制脂肪组的重新仪（反之亦然）。脂质的炎症信号传导水平。促和抗感染的信号如何改变巨噬细胞中细胞下脂质体。光谱法方法，包括shot弹枪脂质组学，纳米X和同位素标记，了解亲和抗炎信号如何影响脂质的定位和贩运巨噬细胞2是确定胆固醇改变的机制增强刺激性信号通路。合成IFN炎症反应通过刺激而变化。方法，共聚焦和纳米菌成像以及化学蛋白质组学，我们将检验以下假设。胆固醇通过直接结合来调节刺激功能。刺激的突变消除了胆固醇的规律性影响。刺激信号通路对血脂异常，炎症的发展的重要性小鼠的动脉粥样硬化已显示出影响动脉粥样硬化的发病机理这种无菌炎症反应的分子途径尚未阐明。假设CGA/STING炎症轴需要在血脂血症和动脉粥样硬化。血脂异常，炎症，免疫细胞浸润和动脉瘤发育。支撑研究将在分子水平上定义为什么巨噬细胞脂质稳态驱动炎症以及炎症如何影响心血管疾病中的巨噬细胞胆固醇代谢。我们的PPG团队对我们的假设感到兴奋，我们的定位是所有的实验方法，试剂和专家合作者，以快速发展。