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

• 批准号: 10375587
• 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
• 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/10375587
• 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; 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; 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; base; design; endoplasmic reticulum stress; epigenome; expectation; fatty acid metabolism; human disease; immune activation; in vivo; lipid metabolism; lipidome; lipidomics; long chain fatty acid; macrophage; member; monocyte; novel; receptor; response; stable isotope; therapeutic target; transcription factor; transcriptomics; western diet

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：研究脂肪酸- crel炎症回路在动脉粥样硬化中的影响