# Pathogenesis in Segmental Demyelination

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2022 · $385,000

## Abstract

Project Summary
Abstract: Segmental demyelination is a pathologic process of stripping off the myelin sheath, which shunts
current out of axons and results in the failure of action potential propagation in a variety of peripheral nerve
diseases. However, the molecular program that leads to demyelination remains unclear, which hampers the
therapeutic development for demyelinating neuropathies. Humans with autosomal recessive mutations in the
FIG4 gene develop Charcot-Marie-Tooth disease type-4J (CMT4J), a disease characterized by segmental
demyelination. Our preliminary studies in a CMT4J mouse model (Fig4−/−) have demonstrated that segmental
demyelination is associated with increased intracellular Ca2+ in myelinating Schwann cells and accumulation
of macrophages in the spinal roots. Administration of a Ca2+ chelator suppresses the demyelination in Fig4−/−
mice. Therefore, this mouse is an appropriate model to investigate the molecular events underlying
demyelination. Toward this end, we will test our central hypothesis that signals from FIG4-deficient axons
and/or macrophages exacerbate the overload of intracellular Ca2+ in FIG4-deficient Schwann cells which, in
turn, leads to segmental demyelination. We propose three Specific Aims to test our hypothesis by determining
if: (1) FIG4-deficient Schwann cells are sensitized to demyelinate upon challenge with Ca2+; (2) FIG4-deficient
macrophages release cytokine IL12B that triggers a further increase in intracellular Ca2+ in FIG4-deficient
Schwann cells, leading to demyelination; and (3) individual proteins in the PAS complex play distinct roles in
the development and maintenance of myelin and axons. These studies have the potential to uncover novel
molecular mechanisms underlying demyelinating peripheral neuropathies and identify targets for therapeutic
development.

## Key facts

- **NIH application ID:** 10518833
- **Project number:** 1R01NS124813-01A1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Bo Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,000
- **Award type:** 1
- **Project period:** 2022-07-15 → 2022-07-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518833

## Citation

> US National Institutes of Health, RePORTER application 10518833, Pathogenesis in Segmental Demyelination (1R01NS124813-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10518833. Licensed CC0.

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