# Regulation of CNS angiogenesis and barriergenesis

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $358,458

## Abstract

The blood-brain barrier (BBB) plays a vital role in diseases of the central nervous system (CNS). Dysfunction of
the BBB is common to several neurological disorders, including stroke, epilepsy, Alzheimer’s disease, and brain
tumors, where brain endothelial cells (BECs) lose barrier properties, gain fenestrations, and increase
permeability. Significantly, the BBB prevents the free exchange of many therapeutic agents, presenting a
challenging problem for the treatment of many neurological diseases. Conversely, when the BBB is compromised
in diseases such as neurodegenerative disorders, brain tumors, stroke, and multiple sclerosis, inflammatory
conditions often result in the infiltration of peripheral immune cells, contributing to the pathology of the disease.
Therefore, a fundamental understanding of BBB formation is essential to provide therapeutic insights into treating
these diseases. During BBB development, there is a coordinated effort between CNS angiogenesis and
barriergenesis (i.e. the acquisition of BBB properties). While both processes are dependent upon signals within
the developing CNS, the precise molecular and cellular mechanisms that drive BBB formation are only beginning
to be elucidated. Our overall objective is to bridge the gap in this knowledge. Our proposal is innovative because
we: 1) identified zebrafish mutants with defective brain vasculature; 2) demonstrated that canonical Wnt signaling
is sufficient for barriergenesis in the absence of Vegf signaling; 3) determined that activated canonical Wnt
signaling in neural progenitor cells inhibits CNS angiogenesis; and 4) identified regulatory elements that may
suppress fenestrations in BECs. Based upon our compelling preliminary studies, our central hypothesis is that
canonical Wnt signaling regulates Vegf signaling and the acquisition of barrier properties in BECs using both cell
autonomous and cell non-autonomous mechanisms. Our specific aims will test the following hypotheses: (Aim
1) canonical Wnt signaling regulates cell autonomous Vegf signaling in BECs, but that Vegf signaling can drive
CNS angiogenesis in the absence of canonical Wnt signaling; (Aim 2) activated canonical Wnt signaling in neural
progenitor cells inhibits the development of the BBB; and (Aim 3) regulatory elements within the plvap promoter
suppress fenestrations in BECs, but not peripheral endothelial cells. Our proposed studies establish an
innovative approach to discover new insights into the molecular and cellular mechanisms that regulate CNS
angiogenesis and barriergenesis. Our long-term goals are to use this information to develop new strategies that
permit the controlled access of therapeutic agents into the CNS and repair damaged or dysfunctional barriers
associated with the pathology of neurological diseases.

## Key facts

- **NIH application ID:** 10143321
- **Project number:** 5R01NS116043-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** MICHAEL ROBERT TAYLOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,458
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143321

## Citation

> US National Institutes of Health, RePORTER application 10143321, Regulation of CNS angiogenesis and barriergenesis (5R01NS116043-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143321. Licensed CC0.

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