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

• Applicant: Privatdozent Dr. Hans-Jörg Hippe
• Subject Area: Cardiology, Angiology ; Pharmacology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 314210641

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.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Michael Rainer Preusch