# Defining TRPV4-mediated cytoskeletal changes that trigger pathological blood-neural barrier disruption

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $484,333

## Abstract

PROJECT SUMMARY/ABSTRACT
TRPV4 (transient receptor potential vanilloid 4) is a calcium-permeable ion channel whose activation has been
implicated in both hereditary and acquired neurological diseases. Gain-of-function mutations cause debilitating
forms of hereditary motor neuron disease and neuropathy/neuronopathy for which no treatment exists. In
addition, increased TRPV4 ion channel activity is implicated in multiple other neurological diseases. While the
association of TRPV4 with disease and the availability of TRPV4 antagonist drugs make TRPV4 a promising
therapeutic target, fundamental aspects of TRPV4 signaling and function remain poorly understood. To
address this knowledge gap, we have generated cellular, fly, and mouse models of TRPV4-associated nerve
disease. Unbiased studies in these models have identified the calcium-regulated actin remodeling proteins
RhoA, CaMKII, and INF2 as critical downstream mediators of TRPV4 signaling. In addition, novel TRPV4
mutant knock-in mice, which develop severe neuromuscular disease that rapidly progresses to death, have
unexpectedly demonstrated that increased TRPV4 activation within neural vascular endothelial cells (ECs)
drives pathological disruption of blood-neural barriers (BNBs). Together, these results suggest that TRPV4
causes neurodegeneration through dysregulation of actin cytoskeletal remodeling in ECs, resulting in BNB
breakdown. As BNB disruption is a common pathological event in a variety of degenerative and traumatic
neurological diseases, effective therapeutic strategies to limit BNB breakdown would have far-reaching clinical
value. Here, we propose a series of complementary studies utilizing in vitro models of neural vascular ECs and
TRPV4 knock-in mice to further define the molecular mechanisms by which TRPV4 modulates the actin
cytoskeleton and BNB integrity. In Specific Aim 1, we will use a combination of dynamic molecular biosensors,
candidate-based biochemical assessments, and unbiased phospho-proteomics to define downstream TRPV4
signaling events and their temporal activation profiles. Specific Aim 2 will address the contribution of the
calcium-sensitive actin remodeling proteins RhoA, CaMKII, and INF2 to TRPV4-mediated calcium influx and
modulation of cellular morphology and BNB integrity. In Specific Aim 3, we will use TRPV4 knock-in mice to
investigate the topographic and temporal patterns of actin modulating protein activation in the context of
TRPV4-mediated BNB disruption. We will also determine the contribution of RhoA and INF2 activity to TRPV4
knock-in phenotypes, including motor behavior, BNB disruption, and survival. Together, these studies will
delineate TRPV4-mediated signaling cascades that modulate cytoskeletal changes and barrier function in
neural vascular ECs. These results will define specific molecular pathways that modulate BNB integrity and
reveal therapeutic opportunities to limit pathological BNB disruption in neurological disease.

## Key facts

- **NIH application ID:** 10877379
- **Project number:** 1R01NS131402-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Brett Andrew McCray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,333
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877379

## Citation

> US National Institutes of Health, RePORTER application 10877379, Defining TRPV4-mediated cytoskeletal changes that trigger pathological blood-neural barrier disruption (1R01NS131402-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10877379. Licensed CC0.

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