# Mechanisms of oligodendroglial ciliary function in white matter injury repair

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $403,750

## Abstract

PROJECT ABSTRACT
After damage to white matter tracts (WMI) in CNS diseases such as multiple sclerosis (MS) in adults and
newborn brain injuries that cause cerebral palsy (CP), myelin sheaths can be regenerated by activated
oligodendrocyte precursor cells (OPCs). Failure of this remyelination program often occurs due to the improper
recruitment of OPCs into injury sites, contributing significantly to ongoing neurological dysfunction and disease
progression. Understanding the mechanisms controlling OPC biology during remyelination will provide insights
as to why myelin repair fails in human cases. Importantly, OPCs dynamically produce primary cilia, microtubule-
based organelles that transduce intercellular cues in a specialized signaling compartment. The role of primary
cilia in regulating developmental pathways in OPCs remains poorly understood. Here, we show that OPCs
require primary cilia to respond properly to WMI. First, this grant will demonstrate that genetically removing
primary cilia from OPCs results in inadequate WMI repair, identifying the primary cilium as a critical
effector of biological change in OPCs necessary for the WMI response. Furthermore, as there remains little
mechanistic understanding of ciliary signaling pathways in OPCs, we will use a combination of approaches that
ultimately define a GPCR/cAMP/CREB signaling axis beginning at the primary cilium as a crucial regulator
of OPC biology. Finally, with recent advances in proximity-labeling, we can now catalogue the proteins that
survey OPC primary cilia using a technique termed cilia-APEX. This grant will utilize cilia-APEX to identify
signaling molecules that localize to OPC primary cilia in vitro and during remyelination in vivo. This will
demonstrate dynamic changes in the protein content of OPC primary cilia during different stages of
remyelination, while also adding significant insight into the extent of ciliary functions in OPCs. Together, these
studies will show that primary cilia are a critical signaling module in OPCs for the regulation of remyelination,
and will reveal potential therapeutic target for conditions such as MS and CP, where the OPC response to injury
can be dysfunctional.
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## Key facts

- **NIH application ID:** 10659990
- **Project number:** 1R01NS128021-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Stephen Philip James Fancy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $403,750
- **Award type:** 1
- **Project period:** 2023-04-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10659990

## Citation

> US National Institutes of Health, RePORTER application 10659990, Mechanisms of oligodendroglial ciliary function in white matter injury repair (1R01NS128021-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10659990. Licensed CC0.

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