IDO1 regulation of SR-BI and cholesterol homeostasis in macrophages

IDO1 对巨噬细胞中 SR-BI 和胆固醇稳态的调节

基本信息

批准号：
10731003
负责人：
Subhrangsu S Mandal
金额：
$ 45.75万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
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：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731003
关键词：
Address Animal Model Animals Aryl Hydrocarbon Receptor Atherosclerosis Biochemical Biological Process Blood Body Weight Cardiovascular Diseases Cells Cholesterol Cholesterol Homeostasis Chronic Complex Diabetes Mellitus Dioxygenases Disease Down-Regulation Endotoxins Environment Estradiol Estrogen Receptors Excision Foam Cells Functional disorder Genes Genotoxic Stress Goals HDL cholesteryl ester Hallmark Cell Health Hemostatic function High Density Lipoproteins Homeostasis Host Defense Hyperlipidemia Hypertension Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Insulin Resistance Kupffer Cells Kynurenine Link Lipids Lipopolysaccharides Lipoprotein Receptor Liver Low Density Lipoprotein Receptor Macrophage Macrophage Activation Mediating Metabolic Diseases Metabolic dysfunction Metabolic syndrome Metabolism Minority-Serving Institution Obesity Ovarian hormone Ovariectomy Pathogenicity Plasma Play Rattus Receptor Activation Receptor Signaling Regulation Repression Research Research Training Role Signal Pathway Signal Transduction Starvation Students Therapeutic Tissues Tryptophan Tryptophan 2,3 Dioxygenase aryl hydrocarbon receptor ligand atheroprotective biological adaptation to stress cardiovascular disorder risk career cytokine experience experimental study high density lipoprotein receptor human disease in vivo lipid metabolism liver inflammation novel potential biomarker receptor scavenger receptor therapeutic target transcriptome sequencing transdifferentiation undergraduate student uptake

项目摘要

Inflammation is a fundamental biological process that plays key roles in immune response. However, uncontrolled, and chronic inflammation are the root causes of many human diseases including metabolic disorders, obesity, insulin resistance, diabetes, hypertension, and atherosclerosis. Macrophage activation plays a central role in inflammation, regulates the host defense during pathogenic infection, and maintain tissue homeostasis. Recent studies indicate that macrophage functions are influenced by lipid metabolism.10-15 The imbalance in lipid uptake, metabolism, and removal in macrophages cause tissue trans-differentiation contributing to hyperlipidemia and metabolic syndrome. For example, macrophages and derived foams cells are the hallmarks of atherosclerosis. The signaling mechanism associated with lipid homeostasis and metabolism in macrophages is complex and poorly understood. The primary goal of this proposal is to investigate the cholesterol homeostasis mechanism in macrophages under inflammation. In particular, HDLR-SR-BI (SR-BI), a receptor for the cholesterol-rich HDL, facilitates the selective delivery of HDL-cholesteryl ester to the liver. It promotes atheroprotection via HDL metabolism. SR-BI is also expressed in in macrophages and regulates lipid homeostasis. In a preliminary study, we observed that the SR-BI expression is downregulated in macrophages upon LPS stimulation, and this is potentially regulated viaIndoleamine-2,3-dioxygenase 1 (IDO1). We found that IDO1 and its down-stream catabolite, kynurenine (KYN), are also elevated in LPS-stimulated macrophages and inhibition of IDO1 reversed the LPS-induced downregulation of SR-BI, suggesting potential role of IDO1 in SR- BI expression and cholesterol homeostasis, in macrophages. Notably, KYN is a ligand for aryl hydrocarbon receptor (AhR) which regulates genotoxic stress and inflammatory response. Here, we propose biochemical and cell-based experiments to investigate the roles of IDO1 and KYN-AhR signaling in SR-BI expression and cholesterol homeostasis, in macrophages (aim 1). In the aim 2, we propose to investigate the roles of IDO1 in hepatic inflammation, Kupffer cells (resident macrophage in liver) activation, SR-BI expression, and cholesterol homeostasis in vivo using ovariectomized (OVX) rat as animal model. Overall, our studies will lead to the discovery of novel signaling pathways associated with SR-BI expression and cholesterol homeostasis in macrophages under inflammation. In addition to addressing an important scientific problem, this proposal will also serve to enrich student (especially undergraduates) research experiences at UTA, a minority-serving institution. 1

炎症是一个基本的生物学过程，在免疫反应中起关键作用。然而，不受控制，慢性炎症是许多人类疾病的根本原因，包括代谢疾病，肥胖，胰岛素抵抗，糖尿病，高血压和动脉粥样硬化。巨噬细胞激活发挥在炎症中起着核心作用，调节病原体感染期间的宿主防御，并保持组织稳态。最近的研究表明，巨噬细胞功能受脂质代谢的影响。10-15 脂质摄取，代谢和去除巨噬细胞的不平衡引起组织反差异导致高脂血症和代谢综合征。例如，巨噬细胞和衍生的泡沫细胞是动脉粥样硬化的标志。与脂质稳态和代谢相关的信号传导机制巨噬细胞很复杂且理解不佳。该提议的主要目标是调查在炎症下巨噬细胞中的胆固醇稳态机制。特别是HDLR-SR-BI（SR-BI），A 富含胆固醇的HDL的受体促进了HDL-golesteryl酯的选择性递送到肝脏。它通过HDL代谢促进动脉保护。 SR-BI在巨噬细胞中也表达并调节脂质稳态。在一项初步研究中，我们观察到巨噬细胞中的SR-BI表达被下调在LPS刺激后，这可能是通过Indoleamine-2,3-二加氧酶1（IDO1）对其进行调节的。我们发现 IDO1及其下游分解代谢物Kynurenine（Kyn）在LPS刺激的巨噬细胞中也升高 IDO1的抑制逆转了LPS诱导的SR-BI下调，这表明IDO1在SR-中的潜在作用巨噬细胞中的BI表达和胆固醇稳态。值得注意的是，Kyn是芳基烃的配体调节遗传毒性应激和炎症反应的受体（AHR）。在这里，我们提出了生化和基于细胞的实验来研究IDO1和Kyn-Ahr信号在SR-BI表达和胆固醇稳态，巨噬细胞（AIM 1）。在目标2中，我们建议研究IDO1在肝炎，库普弗细胞（肝脏中的巨噬细胞）激活，SR-BI表达和胆固醇使用卵巢切除（OVX）大鼠作为动物模型的体内稳态。总体而言，我们的研究将导致发现与SR-BI表达和胆固醇稳态相关的新型信号通路巨噬细胞在炎症下。除了解决一个重要的科学问题外，该建议还将还可以在UTA上丰富学生（尤其是本科生）的研究经验，UTA是少数群体服务的机构。 1