# TRPV4 links the blood-neural barrier to motor neuron dysfunction

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $496,963

## Abstract

PROJECT SUMMARY
Increased permeability of blood-neural barriers (BNBs) has been implicated in the pathogenesis of multiple
acute and chronic neurological disorders, including neurodegenerative disease, but the specific contributions of
BNB impairments to neuronal dysfunction and degeneration have been difficult to pinpoint. During
characterization of patients with inherited forms of motor neuron disease, we and others previously discovered
that autosomal dominant mutations of the cell surface-expressed cation channel transient receptor potential
vanilloid 4 (TRPV4) cause subtypes of spinal muscular atrophy and Charcot-Marie-Tooth disease. While our
studies in cultured cells suggest that TRPV4 mutations cause a gain of channel function, there is little evidence
that TRPV4 is functionally expressed in motor neurons. In order to further dissect the cellular basis of TRPV4
channelopathy, we recently generated novel mutant TRPV4 knock-in mouse models that develop severe
neurological phenotypes associated with focal breakdown of BNBs, particularly in the ventral horn of the
cervical spinal cord and brainstem. Strikingly, cell type-specific genetic deletion of TRPV4 from endothelial
cells (ECs) or treatment of symptomatic mice with a TRPV4 small molecule antagonist markedly reverses
these phenotypes. Together, these studies suggest that TRPV4 activation plays a fundamental role in
regulating BNB integrity and that TRPV4 antagonists could be a novel therapeutic promoting BNB function.
Here, in Specific Aim 1, we will characterize the topographical and temporal expression patterns of TRPV4 in
neural vascular ECs and determine the effects of TRPV4 mutations on TRPV4 channel activity in both cultured
primary mouse neural vascular ECs and human iPSC-derived neural vascular ECs. In Specific Aim 2, we will
determine how TRPV4 activity alters BNB permeability and structure in vitro, including in both 2D confluent
monolayers and in 3D engineered microvessels, as well as in mutant TRPV4 mouse models in vivo. Finally, in
Specific Aim 3, using patch clamp electrophysiology in spinal cord slices, we will determine how BNB leak
affects motor neuron function and structure, and determine whether TRPV4 small molecule antagonists can
reverse disease manifestations in mutant TRPV4 mice. Together, these studies will define a previously
uncharacterized role for TRPV4 in neural vascular ECs in regulating BNB integrity, determine effects of BNB
breakdown on motor neuron function, and investigate whether a TRPV4 small molecule antagonist could be a
novel treatment for patients with TRPV4 mutations, as well as for patients with other neurological diseases
characterized by impaired BNBs.

## Key facts

- **NIH application ID:** 9916170
- **Project number:** 1R01NS115475-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Charlotte Jane Sumner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $496,963
- **Award type:** 1
- **Project period:** 2020-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916170

## Citation

> US National Institutes of Health, RePORTER application 9916170, TRPV4 links the blood-neural barrier to motor neuron dysfunction (1R01NS115475-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9916170. Licensed CC0.

---

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