# Identifying novel targets and mechanistic role of 8,9 unsaturated sterol accumulation on enhancement of oligodendrocyte formation

> **NIH NIH F31** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $12,959

## Abstract

Project Summary
Multiple Sclerosis (MS) is a debilitating disease that is characterized by loss of oligodendrocytes in the brain. A
potential therapeutic angle for MS is through the increased differentiation of oligodendrocyte progenitor cells
(OPCs) into oligodendrocytes. Increasing differentiation of OPCs is a viable therapeutic option because they are
a stem cell population that is found in the adult brain with the ability to differentiate, albeit typically at lower rates
than needed to alleviate the symptoms of MS. Different labs have conducted high throughput screens to identify
novel small molecules that lead to increased OPC differentiation. In work from our lab, we identified a unifying
mechanism of the hits from these screens. Each small molecule inhibited one of three steps within the cholesterol
biosynthesis pathway, which we then identified the accumulation of the 8,9 unsaturated sterols from these steps
as being the mechanism of action. Our lab has evaluated the accumulation of different sterols and the cholesterol
biosynthesis pathway for other novel targets. In this proposal, we plan to elucidate different targets within the
cholesterol biosynthesis pathway and evaluate potential mechanisms by which these sterols enhance
oligodendrocyte formation. In Aim 1, we have developed tools and small molecules to target previously
overlooked enzymes within the cholesterol biosynthesis pathway, SC4MOL, NSDHL, and HSD17B7. Potential
inhibition of these three enzymes would similarly lead to accumulation of 8,9-unsaturated sterols. Therefore, we
hypothesize that these enzymes provide additional therapeutic targets. In Aim 2, we propose that two parallel
pathways within the cholesterol biosynthesis pathway have unique effects on oligodendrocyte differentiation. In
Aim 3, we have identified two potential signaling mechanisms in which 8,9-unsaturated sterols promote OPC
differentiation. Transcriptomic and proteomic analyses have been done to determine different downstream
signaling pathways by which these 8,9-unsaturated sterols act through to promote OPC differentiation. Two
different signaling pathways have been implicated, and this proposal evaluates whether they are the mechanism.
Taken together, the experiments outlined in this proposal will provide key new findings in the search and
development of remyelinating therapeutics. Both new targets (Aim 1 and 2) and the mechanism of these sterols
(Aim 3) will provide a more complete picture and potential therapeutic strategies to target OPCs to repopulate
oligodendrocytes in the brain.

## Key facts

- **NIH application ID:** 10748406
- **Project number:** 5F31NS122176-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Matthew Atala Pleshinger
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $12,959
- **Award type:** 5
- **Project period:** 2021-12-06 → 2023-12-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10748406

## Citation

> US National Institutes of Health, RePORTER application 10748406, Identifying novel targets and mechanistic role of 8,9 unsaturated sterol accumulation on enhancement of oligodendrocyte formation (5F31NS122176-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10748406. Licensed CC0.

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