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

动脉粥样硬化目前被认为是血管壁的炎症过程，在糖尿病和肥胖中加速，导致心血管疾病，表现为心肌梗死和中风。动脉粥样硬化的有效特异性抗炎疗法仍然缺乏。在此，我们提出研究新型葡萄糖敏感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与人类体重指数有关，其果蝇同源基因已被证明可以控制果蝇的能量和脂质代谢。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抗性。我们还发现，GPRC5B的表达受高血糖和炎症细胞因子以及人颈动脉斑块和2型糖尿病患者血液单核细胞的差异调节。在血管壁的内皮细胞和平滑肌细胞中，GPRC5B激活促炎和促动脉粥样硬化途径，包括NFkappaB。当前项目的目的是阐明GPRC5B在动脉粥样硬化发生中的作用。在体内，我们将研究低密度脂蛋白受体敲除（LDLR-KO）小鼠在骨髓移植后以及与转基因和GPRC5B-KO小鼠杂交后的表现。在这些小鼠系中，我们将分析链脲佐菌素诱导的1型糖尿病患者在正常和高血糖状态下动脉粥样硬化斑块的发生和进展。同样，我们将在两种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））后发生的新内膜形成和再狭窄中的作用。在体外，我们将尝试确定gprc5b介导的信号传导的细胞类型特异性机制，特别是同源异三聚体G蛋白和下游效应物及其在高血糖中的修饰。破解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，将有助于我们对动脉粥样硬化的理解，从而使GPRC5B脱形，并为动脉粥样硬化的治疗提供新的抗炎靶点。

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.