Investigating the impact of a fatty acid-cRel inflammatory circuit in atherosclerosis

研究脂肪酸-cRel 炎症回路对动脉粥样硬化的影响

基本信息

批准号：
10591518
负责人：
STEVEN J BENSINGER
金额：
$ 57.37万
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：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591518
关键词：
ATAC-seq Affect Anti-Inflammatory Agents Arterial Fatty Streak Atherosclerosis Attenuated Cardiometabolic Disease Cardiovascular Diseases Cardiovascular system Cells ChIP-seq Cholesterol Homeostasis Chronic Cues Cytokine Signaling Data Data Set Diabetes Mellitus Disease Dyslipidemias Enzymes Epigenetic Process Event Family member Fatty Acids Genetic Models Genetic Transcription Goals Grant Homeostasis Immune In Vitro Inflammation Inflammatory Inflammatory Response Interferons Laboratories Lead Link Lipids Macrophage Maps Mass Spectrum Analysis Metabolic Metabolic Diseases Metabolism Modeling Molecular Monounsaturated Fatty Acids Mus Obesity Pathogenesis Pathogenicity Pathway interactions Phenotype Polyunsaturated Fatty Acids Process Proteins Public Health Reporting Role Saturated Fatty Acids Shapes Shotguns Signal Pathway Signal Transduction TLR2 gene TLR3 gene TLR7 gene Techniques Testing Therapeutic Intervention Tissues Tracer Up-Regulation Vascular Endothelium Work advanced analytics atherogenesis design endoplasmic reticulum stress epigenome expectation fatty acid metabolism human disease immune activation in vivo lipid metabolism lipidome lipidomics long chain fatty acid member monocyte novel programs receptor response stable isotope therapeutic target transcription factor transcriptomics western diet

项目摘要

R01: Investigating the impact of a fatty acid–cRel inflammatory circuit in atherosclerosis ABSTRACT/SUMMARY The objective of this grant to is to understand how inflammation and lipid metabolism are linked via circuits within macrophages, and whether these circuits influence cardiometabolic disease. Although perturbations in lipid homeostasis are recognized to be associated with inflammation in a number of human diseases, our understanding of “how” and “why” the processes are intimately linked remains limited. Recent work has revealed that pro-inflammatory signals can 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 interconnected, and perturbations in one affect the other. In this proposal, we 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). Specific Aim 1 is to determine the mechanisms by which alterations in monounsaturated fatty acid (MUFA) homeostasis regulate inflammation in activated macrophages. Specifically, we will pursue our discovery that blocking de novo MUFA synthesis potentiates inflammatory responses via the NF-κB member cRel. Using a combination of transcriptomics, ATAC- Seq, and ChIP-Seq approaches, we will test the hypothesis that MUFA synthesis regulates inflammatory function by specifically controlling cRel and the reprogramming the epigenome. Specific Aim 2 is focused on advancing our understanding of how reprogramming of lipid metabolism occurs in macrophages, and determining the extent to which reprogramming of lipid metabolism in monocytes and macrophages in vivo. By applying advanced analytic techniques on tissue resident macrophages under normal, inflammatory and dyslipidemic conditions, we will determine whether activation signals and lipid environmental cues can induce or shape lipid metabolic reprogramming in vivo. We also further our understanding of how anti-inflammatory signals or ER stress signals are integrated into this process of metabolic reprogramming. Specific Aim 3 is to determine the impact of the SCD enzymes on dyslipidemia, chronic inflammation, and atherosclerosis in mice. The SCD proteins have been reported to both potentiate and attenuate atherogenesis. We suspect this is due to the complicating factor that there are multiple SCDs. In this aim, we ask if the combined loss of SCD1 and SCD2 specifically in macrophages exacerbate inflammation, dyslipidemia and atherogenesis. Conversely, can enforced SCD expression in monocytes and macrophages protect from disease. Likewise, does loss of cRel ameliorate inflammation and atheroma formation in response to western diet. 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.

R01：研究动脉粥样硬化中脂肪酸 - 尿液炎症回路的影响摘要/摘要这样做的目的是通过内部电路链接到底层巨噬细胞，以及这些电路是否影响心脏代谢疾病。稳态被认为与多种人类疾病的炎症有关对“为什么”过程的理解是近期的启示。那个亲人也变得很清楚。脂质稳态的扰动可以诱导并诱发炎症的炎症。一个扰动会影响另一个提案。基于炎症的遗传模型的方法，其目的是防御机制炎症驱动了脂质组的重编程（反之亦然）。单不饱和脂肪酸（MUFA）稳态调节炎症的改变的机制激活的巨噬细胞。通过NF-κB成员Crel增强炎症反应。 SEQ和CHIP-SEQ方法，我们将测试Muffa合成调节炎症功能的假设通过专门控制弹性和重编程表观基因组。我们理解脂质代谢的重新编程发生在巨噬细胞中，并确定程度通过应用晚期，在单核细胞和巨噬细胞中脂质代谢的重生在正常，炎症和血脂症状条件下，组织驻留巨噬细胞的分析技术，我们将确定激活信号和Lipilonmental提示是否可以诱导或塑造脂质代谢在体内重新摄影。被整合到代谢重编程的过程中。 SCD酶在血脂异常，慢性炎症和小鼠的动脉粥样硬化中。向两个增强的衰减动脉粥样硬化。在此目标中有多个SCD 加剧炎症，血脂异常和动脉粥样硬化。单核细胞和巨噬细胞也可以免受疾病的侵害。动脉瘤响应西方饮食。分子水平，为什么巨噬细胞脂质稳态失调会驱动炎症，以及炎症如何影响巨噬细胞胆固醇代谢在心血管疾病中。