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: 10186282
• 负责人: STEVEN J BENSINGER
• 金额: $ 57.47万
• 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/10186282
• 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.

R 01：研究脂肪酸-cRel炎症回路在动脉粥样硬化中的影响 摘要/总结 这项资助的目的是了解炎症和脂质代谢是如何通过体内的回路联系起来的。 巨噬细胞，以及这些回路是否影响心脏代谢疾病。虽然脂质的扰动 体内平衡被认为与许多人类疾病中的炎症有关，我们 对这些进程“如何”和“为什么”密切相关的理解仍然有限。最近的研究表明， 促炎信号可以重新编程巨噬细胞的脂质代谢状态。也显示 脂质体内平衡的扰动可以被巨噬细胞的炎症机制感知， 诱导和调节炎症反应。因此，脂质稳态和炎症是相互关联的， 其中一个的扰动会影响另一个在这个提议中，我们将联合收割机先进的分析质谱- 基于炎症遗传模型的方法，目的是定义机制， 炎症驱动脂质组的重编程（反之亦然）。具体目标1是确定 单不饱和脂肪酸（MUFA）稳态改变调节炎症的机制， 激活的巨噬细胞具体地说，我们将继续研究我们的发现， 通过NF-κB成员cRel增强炎症反应。使用转录组学的组合，ATAC- Seq和ChIP-Seq方法，我们将检验MUFA合成调节炎症功能的假设 通过特异性控制cRel和重编程表观基因组。具体目标2侧重于推进 我们对巨噬细胞中脂质代谢重编程的理解， 其中在体内单核细胞和巨噬细胞中脂质代谢的重编程。采用先进的 在正常、炎症和血脂异常条件下对组织驻留巨噬细胞的分析技术， 我们将确定激活信号和脂质环境线索是否可以诱导或塑造脂质代谢， 体内重编程我们还进一步了解了抗炎信号或ER应激信号是如何 被整合到这个代谢重编程的过程中。具体目标3是确定 SCD酶对小鼠血脂异常、慢性炎症和动脉粥样硬化的影响。SCD蛋白已经被 据报道既增强又减弱动脉粥样硬化形成。我们怀疑这是由于复杂的因素， 存在多个SCD。在这个目标中，我们问，如果SCD 1和SCD 2的联合损失，特别是在巨噬细胞中， 加重炎症、血脂异常和动脉粥样硬化形成。相反，可以强制SCD表达， 单核细胞和巨噬细胞保护免于疾病。同样，cRel的损失是否改善炎症， 西方饮食引起的动脉粥样硬化形成。我们的期望是，我们提出的研究将确定，在一个 分子水平，为什么巨噬细胞脂质稳态失调驱动炎症，以及炎症如何 在心血管疾病中影响巨噬细胞胆固醇代谢。