# Pathogenesis of TRPV4-related peripheral neuropathy

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2020 · $199,800

## Abstract

PROJECT SUMMARY/ABSTRACT
Charcot-Marie-Tooth (CMT) disease is the most common inherited neurologic disease worldwide and causes
peripheral nerve degeneration with resultant progressive sensory loss and muscle weakness. Despite
identification of over 80 causative genes, CMT lacks treatments due to incomplete understanding of disease
mechanisms and a lack of rational drug targets. Mutations in TRPV4 (transient receptor potential vanilloid), a
calcium-permeable non-selective ion channel, cause CMT type 2C (CMT2C). TRPV4 is unique in that it
represents the only membrane-expressed ion channel in CMT and thus a potential therapeutic target. TRPV4
is known to regulate cytoskeletal changes in epithelial cells, but a similar role in neurons has not been
established. As neuronal cytoskeletal changes are critical for neuronal development and maintenance and are
regulated by calcium signaling, defining the role of TRPV4 in modulating neuronal cytoskeleton has important
implications for the pathogenesis of CMT2C and potentially in other neurodegenerative conditions. Our
collective preliminary work in cells, primary neurons, and flies suggests that TRPV4 can promote neurite
outgrowth, but that this function is disrupted by neuropathy-causing mutations. We have also used unbiased
proteomics to identify TRPV4 interacting proteins, including syndapin-1 and RhoA, which have known roles in
regulating neuronal outgrowth. Specific Aim 1 will define how WT and mutant TRPV4 influence syndapin-1 and
RhoA-dependent cytoskeletal remodeling pathways and examine reciprocal regulation of TRPV4 ion channel
function and mutant toxicity. Specific Aim 2 will address the role of wild type and mutant TRPV4 in regulating
neuronal morphogenesis in primary sensory and motor neurons. In Specific Aim 3, we will use a Drosophila
model of TRPV4 neuropathy and our recently generated TRPV4 mutant knockin mice to interrogate the in vivo
effects of neuropathy mutations. We will also examine whether genetic manipulation of RhoA and syndapin or
pharmacologic manipulation of TRPV4 channel activity can alter neuronal phenotypes in flies. The experiments
in this proposal will define the normal function of TRPV4 in neuronal cytoskeletal remodeling and
morphogenesis, investigate specific pathogenetic mechanisms in TRPV4 neuropathy, and determine whether
TRPV4 can be therapeutically targeted in vivo. Together, these studies will provide important insights into the
role of TRPV4 in axonal health and disease and will inform future efforts to develop TRPV4-based therapeutic
strategies for CMT2C and perhaps other forms of axonal neuropathy.

## Key facts

- **NIH application ID:** 9980503
- **Project number:** 5K08NS102509-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Brett Andrew McCray
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,800
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980503

## Citation

> US National Institutes of Health, RePORTER application 9980503, Pathogenesis of TRPV4-related peripheral neuropathy (5K08NS102509-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980503. Licensed CC0.

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