# Regulation of sphingolipid biosynthesis in central nervous system myelination

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $426,938

## Abstract

Project Summary
The objective of this application is to fill a major gap in the understanding of the formation and
maintenance of the myelin membrane that ensheaths axons in the central and peripheral nervous
systems. The myelin sheath is essential for sustaining the speed of neuronal transmission and for maintaining
neuronal viability. Loss of myelin underlies a number of devastating neuronal diseases such as multiple
sclerosis and so understanding how this specialized membrane is formed and maintained will have direct
application to developing treatments for these diseases. Myelin is composed of a distinct set of proteins and
lipids. While the mechanisms that regulated the production of myelin proteins is becoming well
understood, the mechanisms that control the synthesis of the essential lipid components of myelin
have not been addressed. The goal of the proposed studies is to fill that gap. The laboratory of one of the
PIs guiding this application has pioneered the study of a set of proteins known as the ORMDLs, which are
essential regulators of the synthesis of sphingolipids, a class of lipids essential for myelin formation and
function. The ORMDLs keep sphingolipid production in check, their deletion results in unregulated production
of these lipids. Recently it was reported that a whole-animal knockout of ORMDLs exhibited a neurological
phenotype that was accompanied by myelination defects. Here we directly examine the role of ORMDL
regulation of sphingolipid biosynthesis in the myelin-producing cells of the central nervous system.
We focus on ORMDL3, one of the three ORMDL isoforms. Whole animal deletion of this isoform results in
elevated sphingolipids in the brain. To accomplish our goal we will use two novel mouse lines. One mouse line
will have ORMDL3 deleted throughout life in oligodendrocytes, the myelin-producing cells in the central
nervous system. This line will test ORMDL function during myelin formation. The second mouse line allows us
to delete ORMDL3 in oligodendrocytes in the adult animal to test whether ORMDL3 is required to maintain
myelin. Animals with an ORMDL3 deletion will be examined for myelin lipid and protein composition by
biochemical analysis. The structure of myelin will be examined by electron microscopy as well has by
immunohistochemical analysis. Immunohistochemistry will also be used to determine effects on
oligodendrocyte differentiation, numbers, and viability. These morphological analyses will be complemented by
electrophysiological measurements that will assess changes in the numbers of myelinated axons and effects
on myelin function in promoting conduction velocity. A cell culture model of oligodendrocyte differentiation,
utilizing siRNA knockdown of ORMDL3 in primary oligodendrocytes will complement whole animal studies of
the role of ORMDL3 on oligodendrocyte differentiation and viability. Finally the experimental autoimmune
encephalomyelitis model, which mimics aspects of multiple sclerosis, will be ...

## Key facts

- **NIH application ID:** 10110069
- **Project number:** 1R21NS120128-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** BABETTE FUSS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $426,938
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110069

## Citation

> US National Institutes of Health, RePORTER application 10110069, Regulation of sphingolipid biosynthesis in central nervous system myelination (1R21NS120128-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10110069. Licensed CC0.

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