# Regulation of Blood-Brain Barrier Function by the RECK/GPR124/Wnt7 Pathway

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $354,948

## Abstract

This application investigates regulation of central nervous system (CNS) angiogenesis
and BBB integrity by the membrane protein Reck, a glycophosphatidylinositol (GPI)-
anchored protein with large extracellular domain (ECD). In a fascinating convergence of
data from many groups including ourselves, substantial overlap exists between the
knockout mouse phenotypes for Reck, the G protein-coupled receptor family member
Gpr124 and the Wnt7a/7b ligands. These phenotypes are all unified by marked deficits
in developmental CNS angiogenesis with glomeruloid vascular malformations and
forebrain-specific embryonic lethal hemorrhage. Further, Reck and Gpr124
synergistically promote canonical Wnt signaling with pronounced specificity for Wnt7a/7b
and not other Wnt family members. Here, we perform mechanistic exploration of the
contribution of Reck to Gpr124- and Wnt7a/7b-mediated signaling and blood-brain
barrier (BBB) function.
Here we investigate regulation of BBB integrity by the RECK/GPR124/Wnt
pathway in vitro and in vivo. Aim 1 biochemically characterizes RECK/GPR124-
regulated Wnt7a/7b signaling by defining domains of Reck and Gpr124 that underlie
their physical interaction and functional promotion of Wnt7a/7b signaling. Aim 1 also
investigates potential complex formation with Wnt7a/7b and the established Wnt
receptors Frizzled (Fzd) and LRP. Aim 2 creates an in vitro culture model of the
RECK/GPR124/Wnt pathway using primary brain endothelial cells (ECs) isolated from
genetically modified mice and analyzes effects of pathway modulation on BBB marker
expression and function. Aim 3 investigates the role of the RECK/GPR124/Wnt
pathway in BBB integrity post-stroke using endothelial-specific and inducible knockout of
Reck genetically modified mice and the tMCAO stroke model, and superimposed effects
of Gpr124 knockout or Wnt pathway manipulation. Overall, these studies utilize
complementary biochemical, cell biological, and genetic strategies to explore
RECK/GPR124/Wnt7 regulation of Wnt/β-catenin signaling and BBB function.

## Key facts

- **NIH application ID:** 9959521
- **Project number:** 5R01NS100904-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** CALVIN J KUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,948
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959521

## Citation

> US National Institutes of Health, RePORTER application 9959521, Regulation of Blood-Brain Barrier Function by the RECK/GPR124/Wnt7 Pathway (5R01NS100904-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9959521. Licensed CC0.

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