The normal functioning of the adult brain is critically dependent upon an adequate blood supply. The current project will investigate the role of the orphan G-protein coupled receptor GPR124 during adult angiogenesis in the CNS. We have found that GPR124 knockout mice exhibit embryonic lethality at E15.5 from a profound block and highly CNS-specific block in developmental angiogenesis, with formation of forebrain glomeruloid vascular malformations and hemorrhage. We have now generated Tie2- GPR124 transgenic mice in which GPR124 is overexpressed in CNS endothelium under the control of the Tie2 promoter/enhancer. Despite concomitant ectopic GPR124 expression in non-CNS vasculature, the Tie2-GPR124 mice remarkably develop CNS- specific vascular malformations with enlarged, dilated, hyperproliferative vessels. These further reinforce the CNS vascular tropism of this receptor through an independent, complementary gain-of-function approach. The current project will explore the role of GPR124 in adult angiogenesis in the CNS.
Aim 1 will exploit our newly developed GPR124 conditional knockout mice to examine the role of this receptor during adult CNS angiogenesis induced by VEGF, or by ischemia in a MCAO ligation model.
In Aim 2, the nature of the CNS vascular malformations in Tie2-GPR124 transgenic mice will be further investigated at the level of temporal onset and arteriovenous characteristics. Finally, Aim 3 will model GPR124 signaling in vitro using GPR124-deficient endothelium and putative ligand sources. These studies overall should provide further insight into the role of GPR124 in adult angiogenesis, with particular emphasis on pathophysiologic settings such as stroke and CNS vascular malformations.
PI: Kuo, Calvin J. Project Narrative The blood vessels of the brain are critically important to convey nutrients and oxygen and to maintain optimal brain function. We will study a new receptor and its role in controlling adult blood vessel growth towards developing new therapies for conditions such as stroke and brain vascular malformations.
|Chang, Junlei; Mancuso, Michael R; Maier, Carolina et al. (2017) Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat Med 23:450-460|
|Noda, Makoto; Vallon, Mario; Kuo, Calvin J (2016) The Wnt7's Tale: A story of an orphan who finds her tie to a famous family. Cancer Sci 107:576-82|
|Tsai, Hui-Hsin; Niu, Jianqin; Munji, Roeben et al. (2016) Oligodendrocyte precursors migrate along vasculature in the developing nervous system. Science 351:379-84|
|Lange, Christian; Turrero Garcia, Miguel; Decimo, Ilaria et al. (2016) Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis. EMBO J 35:924-41|
|Chan, Charles K F; Seo, Eun Young; Chen, James Y et al. (2015) Identification and specification of the mouse skeletal stem cell. Cell 160:285-98|
|Hong, Guosong; Diao, Shuo; Chang, Junlei et al. (2014) Through-skull fluorescence imaging of the brain in a new near-infrared window. Nat Photonics 8:723-730|
|Vallon, Mario; Chang, Junlei; Zhang, Haijing et al. (2014) Developmental and pathological angiogenesis in the central nervous system. Cell Mol Life Sci 71:3489-506|
|Wei, Kevin; Piecewicz, Stephanie M; McGinnis, Lisa M et al. (2013) A liver Hif-2?-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nat Med 19:1331-1337|
|Taniguchi, Cullen M; Finger, Elizabeth C; Krieg, Adam J et al. (2013) Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nat Med 19:1325-30|
|Weinsheimer, Shantel; Brettman, Ari D; Pawlikowska, Ludmila et al. (2012) G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation. Transl Stroke Res 3:418-27|
Showing the most recent 10 out of 11 publications