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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064517-03
Application #
8256778
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Owens, David F
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$354,085
Indirect Cost
$139,710
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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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
Kuhnert, Frank; Mancuso, Michael R; Shamloo, Amir et al. (2010) Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science 330:985-9