Investigating the Novel Roles of FFAR4 in Foam Cell Formation and Atherosclerosis

研究 FFAR4 在泡沫细胞形成和动脉粥样硬化中的新作用

基本信息

批准号：
10676531
负责人：
Gage M Stuttgen
金额：
$ 4.77万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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：
2023-04-07 至 2026-04-06
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676531
关键词：
ATP binding cassette transporter 1 Adipocytes Agonist Anti-Inflammatory Agents Aorta Area Arterial Fatty Streak Arteries Atherosclerosis Attention Biological Process Blood specimen Bone Marrow Transplantation CD36 gene Cardiovascular Diseases Cause of Death Cell Nucleus Cholesterol Cytoplasm Data Development Diabetes Mellitus Disease Endothelial Cells Experimental Designs Fasting Foam Cells Future G-Protein-Coupled Receptors Harvest Homeostasis Image Incubated Infiltration Inflammation Inflammatory Inflammatory Response Knockout Mice Lipids Literature Low Density Lipoprotein Receptor Macrophage Measures Mediating Metabolic Mus Nonesterified Fatty Acids Outcome Pathway interactions Peritoneal Macrophages Phosphorylation Physiological Play Prevention Process Property Proteins Publishing Research Role Severities Signal Pathway Signal Transduction Testing United States Unsaturated Fatty Acids Wild Type Mouse atheroprotective cardioprotection cholesterol transporters cytokine design experimental study immune activation in vivo insulin sensitivity lipid biosynthesis migration new therapeutic target novel obesity prevention oxidized low density lipoprotein prevent receptor therapeutic target transcription factor uptake western diet

项目摘要

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the United States. Atherosclerosis, a major cause of CVD, is an inflammatory disease resulting from the build-up of cholesterol in plaque along the artery walls. These plaques are formed by accumulation of macrophage foam cells as an inflammatory response to oxidized low-density lipoprotein (oxLDL) in damaged endothelial cells. Free fatty acid receptor 4 (FFAR4), also known as G-protein coupled receptor 120 (GPR120), is a long-chain unsaturated fatty acid receptor expressed in adipocytes, endothelial cells, and macrophages. Activation of FFAR4 helps maintain metabolic homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. While FFAR4 is best known for its protective role in preventing obesity and diabetes, recent studies have demonstrated that FFAR4 may also play an important role in the prevention of atherosclerosis and CVD. Given FFAR4’s importance in anti-inflammatory signaling and high expression levels in macrophages, we designed experiments to test the hypothesis that FFAR4 plays a cardioprotective role by preventing pathways that lead to atherosclerosis. These experiments will require macrophages harvested from wild-type and FFAR4-knockout mice, and in some cases, macrophages treated with FFAR4 agonists. In Aim 1, we will investigate the effects of FFAR4 deficiency on macrophage foam cell formation. Specifically, we will determine whether FFAR4 deficiency increases oxLDL uptake (Aim 1.1), decreases cholesterol efflux (Aim 1.2), and decreases macrophage migration (Aim 1.3). In Aim 2, we will investigate the signaling mechanisms utilized by FFAR4 to protects against foam cell formation and test the hypothesis that canonical Gaq/11 FFAR4 signaling reduces cholesterol uptake and promotes cholesterol efflux by inhibiting the transcription factor PPARg. In Aim 3, we will investigate the physiological role of FFAR4 in atherosclerosis. Aim 3.1 will examine how FFAR4 deficiency in vivo impacts lipid levels and circulating inflammatory cytokines. Aim 3.2 will assess atherosclerotic lesion size differences and immune cell activation status in the aorta of LDLR-/- mice following transplantation of bone marrow from FFAR4+/+ or FFAR4-/- mice. The outcomes of these proposed studies will uncover the biological functions of FFAR4 and mechanisms that underlie how FFAR4 protects against macrophage foam cell formation, a hallmark of atherosclerosis. Ultimately, our combined current and future studies may identify FFAR4 as a novel therapeutic target for atherosclerosis.

项目摘要/摘要心血管疾病（CVD）是美国死亡的主要原因。动脉粥样硬化，主要原因 CVD的是一种炎症性疾病，是由于沿着动脉壁的斑块中胆固醇堆积而产生的。这些斑块是由巨噬细胞泡沫细胞积累而形成的，作为对氧化的炎症反应损伤内皮细胞中的低密度脂蛋白（OXLDL）。游离脂肪酸受体4（FFAR4），也称为 G蛋白偶联受体120（GPR120）是一种长链不饱和脂肪酸受体，在脂肪细胞，内皮细胞和巨噬细胞。 FFAR4的激活有助于维持代谢稳态调节脂肪生成，胰岛素敏感性和炎症。虽然FFAR4以其保护作用而闻名在预防肥胖和糖尿病方面，最近的研究表明，FFAR4也可能发挥重要作用预防动脉粥样硬化和CVD中的作用。考虑到FFAR4在抗炎信号传导中的重要性和巨噬细胞中的高表达水平，我们设计了实验来检验FFAR4扮演的假设通过防止导致动脉粥样硬化的途径，心脏保护作用。这些实验需要从野生型和FFAR4敲除小鼠收获的巨噬细胞，在某些情况下，巨噬细胞处理过与FFAR4激动剂。在AIM 1中，我们将研究FFAR4缺乏症对巨噬细胞泡沫细胞的影响组成。特别是，我们将确定FFAR4缺乏症是否会增加OXLDL的吸收（AIM 1.1），，在AIM 2中，我们将研究FFAR4使用的信号传导机制，以防止泡沫细胞形成并测试假设Canonical GAQ/11 FFAR4信号传导可降低胆固醇的摄取，并通过抑制转录因子PPARG。在AIM 3中，我们将研究FFAR4在动脉粥样硬化。 AIM 3.1将研究FFAR4缺乏体内如何影响脂质水平和循环炎症细胞因子。 AIM 3.2将评估动脉粥样硬化病变尺寸差异和免疫细胞激活从FFAR4+/+或FFAR4-/ - 小鼠移植骨髓后，LDLR - / - 小鼠主动脉的状态。这这些提出的研究的结果将发现FFAR4的生物学功能和机制 FFAR4如何保护巨噬细胞泡沫细胞形成是动脉粥样硬化的标志。最终，我们的当前和未来研究可能会识别FFAR4是动脉粥样硬化的新型热靶标。