# The role of tissue nonspecific alkaline phosphatase in brain endothelial cell homeostasis

> **NIH NIH R01** · WEST VIRGINIA UNIVERSITY · 2021 · $541,783

## Abstract

PROJECT SUMMARY
The objective of this application is to determine how tissue nonspecific alkaline phosphatase (TNAP) enzymatic
activity maintains cerebrovascular function within the neurovascular unit (NVU). Brain microvascular endothelial
cells (BMECs) comprise the cerebral microvasculature and serve as the structural foundation of the blood-brain
barrier (BBB) and. Increased permeability and diminished integrity of BMECs are two common mechanisms
through which cerebrovascular function is compromised in human disease. TNAP is a highly enriched enzyme
in cerebral microvessels whose function in brain BMECs is poorly understood. Our preliminary data demonstrate
that TNAP activity stimulates a novel signaling mechanism which protects against the loss of cerebral
microvascular integrity and permeability. These intriguing findings led us to propose the central hypothesis that
TNAP maintains NVU homeostasis during cerebral ischemia by preserving BBB integrity. We will utilize mice
with a VE-cadherin-Cre driven conditional deletion of TNAP in endothelial cells (VEcKO) and its wild type
littermates to interrogate the role of TNAP in BMECs. We will compare responses in young (4-5 months) and
aged (18-20 months) mice to assess the age-dependent effects of brain endothelial TNAP on indices of brain
endothelial barrier permeability combined with vascular network analysis and functional behavioral outcomes.
Aim 1 will elucidate the contribution of brain endothelial cell TNAP to NVU dysfunction in ischemic stroke in
young mice. We will employ the transient middle artery occlusion model to assess quantitative differences in
cerebrovascular outcomes and behavioral indices. Aim 2 will determine the impact of brain endothelial cell TNAP
on age-dependent impairment of the NVU. This aim will assess the impact TNAP on BMEC function in aging
and the putative age-dependent interactions in ischemic stroke. Aim 3 will determine how the TNAP-Rho
associated kinase (ROCK) pathway regulates the barrier function and whether pharmacological inhibition of the
ROCK pathway protects against the loss of barrier integrity and functional deficits associated ischemic stroke in
both young and aged mice. Taken together, the studies in this proposal will delineate a novel mechanism through
which brain endothelial cell TNAP enzyme activity preserves NVU function in ischemic stroke and improves
functional recovery post-stroke. The overall results will contribute to our limited understanding of the basic
biology of TNAP’s role at the BBB and its contribution to NVU homeostasis in human health and disease.

## Key facts

- **NIH application ID:** 10220574
- **Project number:** 1R01AG068155-01A1
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Candice Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $541,783
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220574

## Citation

> US National Institutes of Health, RePORTER application 10220574, The role of tissue nonspecific alkaline phosphatase in brain endothelial cell homeostasis (1R01AG068155-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220574. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*