The neurovascular unit (NVU) consists of the brain endothelium, along with associated glia, pericytes and neurons. The molecular definition of mediators of cell-cell interaction between these cell types should yield significant insight into vascular function during physiologic and pathologic processes in the CNS. We have constructed a mouse knockout of GPR124, an orphan G-protein coupled receptor originally identified by its overexpression in tumor endothelium. Inactivation of GPR124 by replacement with a lacZ reporter gene results in embryonic lethality with hemorrhage which is strikingly restricted to the brain. Initial analysis of the mutant CNS microvasculature has revealed profound defects of angiogenic migration and sprouting, while expression analysis of GPR124 indicates expression is highly selective for CNS vasculature. The GPR124 phenotype is highly suggestive of defective paracrine signaling within cells of the neurovascular unit, resulting in improper angiogenesis. In the current proposal, the functions of GPR124 will be explored taking advantage of GPR124 knockout mice which we have created. First, the structure of aberrant vasculature in GPR124-/- mice will be studied with respect to qualitative and quantitative deficiencies of with other cells of the NVU, cellular junctions and extracellular matrix. Second, genetic epistatic relationships will be sought between GPR124 and other genes whose knockouts have similar phenotypes, such as integrins and Id transcriptional repressers. Third, cell types of the neurovascular unit, such as glia, pericytes and neurons, will be systematically tested for the ability to elicit GPR124-dependent responses in tissue culture. Finally, conditional approaches to GPR124 inactivation will be pursued using adenoviral and conditional knockout strategies, to facilitate the eventual study of GPR124 function in fully adult organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS052830-04S1
Application #
7912455
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (90))
Program Officer
Owens, David F
Project Start
2005-07-15
Project End
2010-09-29
Budget Start
2009-09-30
Budget End
2010-09-29
Support Year
4
Fiscal Year
2009
Total Cost
$137,293
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
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
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
Lin, Shuei-Liong; Chang, Fan-Chi; Schrimpf, Claudia et al. (2011) Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol 178:911-23
Stankunas, Kryn; Ma, Gene K; Kuhnert, Frank J et al. (2010) VEGF signaling has distinct spatiotemporal roles during heart valve development. Dev Biol 347:325-36
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
Chan, Charles K F; Chen, Ching-Cheng; Luppen, Cynthia A et al. (2009) Endochondral ossification is required for haematopoietic stem-cell niche formation. Nature 457:490-4
Mancuso, Michael R; Kuhnert, Frank; Kuo, Calvin J (2008) Developmental angiogenesis of the central nervous system. Lymphat Res Biol 6:173-80
Kuhnert, Frank; Tam, Betty Y Y; Sennino, Barbara et al. (2008) Soluble receptor-mediated selective inhibition of VEGFR and PDGFRbeta signaling during physiologic and tumor angiogenesis. Proc Natl Acad Sci U S A 105:10185-90
Kuhnert, Frank; Mancuso, Michael R; Hampton, Jessica et al. (2008) Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126. Development 135:3989-93

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