# Molecular and Cellular Mechanisms of Chromosome 18q23 Dysmyelination

> **NIH NIH R03** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $116,250

## Abstract

ABSTRACT
Suboptimal myelination of the brain, whether developmental or degenerative, has major
ramifications on function. Abnormal myelin slows nerve conduction and signal synchronicity with
consequences such as seizures, intellectual disability, autism and accelerated age-related
cognitive decline. We have identified an approximately 1.6 megabase region of human
chromosome 18q23 that when hemizygous results in a failure of myelin to develop normally.
However, it is not yet known if the cause of this dysmyelination is due to haploinsufficiency of one
of the gene products or a synergistic effect of more than one gene in the critical genomic region.
In this proposal, we have created a team of both clinical and basic scientists to address this
question. Together, we will acquire sufficient data to formulate a successful experimental system
to define the cellular consequences of the causal genetic defect(s) at 18q23 on oligodendrocyte
proliferation, maturation and myelin function both in mice and in human in vitro models. We will
develop an integrated pipeline to perform rescue experimentation in human and mouse models
that will lead to development of high throughput assays for drug screening experiments in which
to test successful compounds on correcting or improving the dysmyelination defect at key stages
of development. For this project, we will generate induced pluripotent stem cells (iPSC) from 3
individuals who are mosaic for a chromosome 18q23 deletion thereby creating sets of isogenic
positive and negative control lines. From these we will derive myelinating cortical spheroid models
to comprehensively evaluate for myelination abnormalities as compared to their controls with
genomic background that differs only at the 18q23 locus. At the same time we will use siRNA
silencing of the conserved 18q23 genes in mouse brain cells to define roles in myelinogenesis
and compare to the myelin characteristics observed in the human 18q23- model. Correlation of
the human and mouse data are essential in order to develop a live mouse model that recapitulates
the human condition and can then be used for drug toxicity and effectiveness screening in
combination with the human in vitro models. In turn, the longitudinal program of the Chromosome
18 Clinical Research Center maintains close contact with the largest cohort of individuals with
chromosome 18 abnormalities, thus making it well positioned to inform interpretation of
experimental results as well as conduct clinical trials based on findings from these results.

## Key facts

- **NIH application ID:** 10873776
- **Project number:** 5R03HD108551-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** JANNINE De Mars CODY
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $116,250
- **Award type:** 5
- **Project period:** 2023-06-23 → 2026-05-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873776

## Citation

> US National Institutes of Health, RePORTER application 10873776, Molecular and Cellular Mechanisms of Chromosome 18q23 Dysmyelination (5R03HD108551-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10873776. Licensed CC0.

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