The role of the glucose-sensitive G protein-coupled orphan receptor GPRC5B in atherogenesis

葡萄糖敏感G蛋白偶联孤儿受体GPRC5B在动脉粥样硬化形成中的作用

• 批准号: 314210641
• 负责人: Privatdozent Dr. Hans-Jörg Hippe
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Pulmologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/314210641?language=en
• 关键词: role; glucose; sensitive; protein; coupled

Atherosclerosis is currently known as an inflammatory process of the vascular wall, accelerated in diabetes mellitus and obesity, leading to cardiovascular disease, manifested as myocardial infarction and stroke. Efficient specific anti-inflammatory therapies for atherosclerosis are still missing. Here, we propose to investigate the novel glucose-sensitive G protein-coupled orphan receptor GPRC5B in the pathogenesis of atherosclerosis. GPRC5B has been associated with body mass index in humans and its drosophila ortholog has been shown to control energy and lipid metabolism in drosophila. GPRC5B-KO mice were resistant to diet-induced obesity and insulin resistance as a result of decreased inflammatory signaling in adipose tissue. We have additionally shown that GPRC5B expression is differentially regulated by hyperglycemia and inflammatory cytokines as well as in human carotid plaques and in blood monocytes from patients with type 2 diabetes. In endothelial and smooth muscle cells of the vascular wall, GPRC5B activates pro-inflammatory and pro-atherogenic pathways, including NFkappaB. The aim of the current project is to elucidate the role of GPRC5B in atherogenesis. In vivo, we will study LDL-receptor knockout (LDLR-KO) mice following bone marrow transplantation from as well as after cross breeding with transgenic and GPRC5B-KO mice. In these mouse lines, we will analyze initiation and progression of atherosclerotic plaques under normo- and hyperglycemia in streptozotocin-induced type 1 diabetes. Similarly, we will investigate GPRC5B in neointima formation and restenosis occurring after vascular trauma such as percutaneous intervention (e.g. balloon injury) in both GPRC5B mouse lines. In vitro, we will try to identify cell type specific mechanisms of GPRC5B-mediated signaling, particularly the cognate heterotrimeric G proteins and downstream effectors and their modification by hyperglycemia. Deciphering the mechanisms and functions of GPRC5B-mediated signal transduction in vascular and monocyte inflammation will add to our understanding of atherogenesis, thereby deorphaning GPRC5B, and suggesting novel anti-inflammatory targets for the treatment of atherosclerosis.

动脉粥样硬化目前被认为是一种血管壁的炎症过程，在糖尿病和肥胖症中加速，导致心血管疾病，表现为心肌梗死和中风。针对动脉粥样硬化的有效的特效抗炎疗法仍然缺乏。在这里，我们建议研究新的葡萄糖敏感的G蛋白偶联孤儿受体GPRC5B在动脉粥样硬化发病机制中的作用。GPRC5B与人类的体重指数有关，它的果蝇同源基因已被证明控制果蝇的能量和脂肪代谢。由于脂肪组织中炎症信号的减少，GPRC5B-KO小鼠对饮食诱导的肥胖和胰岛素抵抗具有抵抗力。此外，我们还发现GPRC5B的表达受高血糖和炎性细胞因子以及人类颈动脉斑块和2型糖尿病患者血单核细胞的差异调节。在血管壁的内皮和平滑肌细胞中，GPRC5B激活了促炎和促动脉粥样硬化的途径，包括NFkappaB。本项目的目的是阐明GPRC5B在动脉粥样硬化形成中的作用。在体内，我们将研究低密度脂蛋白受体基因敲除(LDLR-KO)小鼠，包括转基因小鼠和GPRC5B-KO小鼠的骨髓移植和杂交。在这些小鼠中，我们将分析在正常血糖和高血糖条件下，链脲佐菌素诱导的1型糖尿病患者动脉粥样硬化斑块的发生和发展。同样，我们将在两个GPRC5B小鼠系中研究GPRC5B在血管创伤(如经皮介入治疗(如球囊损伤)后发生的新生内膜形成和再狭窄中的作用。在体外，我们将试图确定GPRC5B介导的信号转导的细胞类型特异性机制，特别是同源异三聚体G蛋白和下游效应蛋白及其高血糖对它们的修饰。破译GPRC5B介导的信号转导在血管和单核细胞炎症中的机制和功能将有助于我们理解动脉粥样硬化的发生，从而使GPRC5B去孤儿，并为治疗动脉粥样硬化提供新的抗炎靶点。