# Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $382,090

## Abstract

ABSTRACT
Loss of oligodendrocytes gives rise to demyelination, ultimately resulting in axonal degeneration and debilitating
clinical outcomes in diseases like Multiple Sclerosis. While remyelination can prevent neurodegeneration, there
are currently no approved therapies for promoting remyelination. Thus, there is an urgent need to identify factors
that control remyelination. Neural stem cells in the adult subventricular zone are one of the sources of
remyelinating oligodendrocytes. These cells are a heterogeneous population that show diverse responses to
signaling pathways in the healthy vs demyelinated brain. We have studied one such pool marked by Gli1, which
generates remyelinating oligodendrocytes only in response to demyelination. Our previous work showed that the
recruitment and differentiation into oligodendrocytes leading to functional recovery is increased substantially by
loss of Gli1 in this pool of neural stem cells; however the molecular mechanisms involved in this repair is not
known. Through a transcriptomic analysis comparing gene expression in neural stem cells with and without Gli1
expression, we identified the TGFβ1 pathway as a major regulator of remyelination mediated by neural stem
cells. However, the effects of TGFβ1 signaling are context dependent and differ with the cell-type, timing and
dosage suggesting the presence of specific modulators of the pathway in different cells. Using a combination of
bioinformatic analysis and remyelination studies in mice, we discovered a novel mediator of the TGFβ1 pathway,
Gpnmb which is highly expressed along with its receptor CD44 in neural stem cells in response to demyelination.
In the first aim, we will define the cell-autonomous function of Gpnmb in neural stem cells and its role in
remyelination by neural stem cells. In the second aim, we will determine the impact of paracrine Gpnmb signaling
through CD44 receptor on remyelination mediated by neural stem cells. In the third aim, we will elucidate the
mechanisms of regulation of Gpnmb by TGFβ1 ligand and reciprocal modulation of the TGFβ1 pathway by
Gpnmb. For the remyelination studies, we will use the toxin induced models of demyelination. To define the
molecular mechanisms of the TGFβ1-Gpnmb signaling pathway, we will utilize in vitro neural stem cell cultures
from adult mouse brain. Together, these studies will help identify therapeutic targets for promoting remyelination.

## Key facts

- **NIH application ID:** 10366677
- **Project number:** 1R01NS119517-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Jayshree Samanta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,090
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366677

## Citation

> US National Institutes of Health, RePORTER application 10366677, Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells (1R01NS119517-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10366677. Licensed CC0.

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