# CNS Demyelination: Initiation, Protection, and Correction

> **NIH NIH R35** · NORTHWESTERN UNIVERSITY · 2024 · $780,341

## Abstract

Project Summary
The loss of CNS myelin, which is produced and maintained by oligodendrocytes, is a critical aspect of a wide
range of neurological conditions and results in the altered electrophysiology of the damaged axonal unit.
Moreover, the resulting myelin debris impede intrinsic efforts to remyelinate the demyelinated axons, and these
debris, which are engulfed by microglia, also activate an innate immune response, leading to further inflammatory
CNS damage. The studies described in this proposal are centered on three aspects of demyelination: activation,
the process by which oligodendrocytes are damaged; protection, the effort to shield oligodendrocytes from
factors that lead to their dysfunction and/or demise; and correction, the process by which demyelinated axons
are remyelinated. This R35 proposal represents a convergence of four separate, NINDS-supported, studies
centered on various aspects of the function and dysfunction of oligodendrocytes. This umbrella award will allow
us to focus our energy on how our understanding of oligodendrocyte biology, gained through these awards, can
be channeled into a deeper understanding of the harmful impact of demyelination on the CNS, as well as how
this damage can be reduced and repaired. These efforts will benefit from access to the inducible, genetic,
oligodendrocyte ablation mouse model (DTA) that we developed. In addition to providing a model of acute
oligodendrocyte loss and demyelination followed by robust remyelination, DTA mice develop a late-onset,
autoimmune demyelinating stage that mimics various aspects of progressive multiple sclerosis. Oligodendrocyte
protection by the integrated stress response (ISR) has been a major theme of our research efforts for over two
decades, and we will extend this line of research in the proposed studies. Moreover, our funded studies have
uncovered the critical role of the zinc finger protein ZFP24, as well as the reversible methylation of mRNA, in the
molecular control of oligodendrocyte development and function. These insights will benefit our efforts to better
understand and enhance the CNS remyelination process. Together, our planned studies should significantly
advance our understanding of the causes and consequences of demyelination and remyelination, which are of
considerable relevance to a wide range of neurological disorders that result in disrupted CNS myelin.

## Key facts

- **NIH application ID:** 10893814
- **Project number:** 1R35NS137478-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Brian J Popko
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $780,341
- **Award type:** 1
- **Project period:** 2024-05-15 → 2032-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893814

## Citation

> US National Institutes of Health, RePORTER application 10893814, CNS Demyelination: Initiation, Protection, and Correction (1R35NS137478-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10893814. Licensed CC0.

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