# Pathological Mechanotransduction by Oligodendrocytes After Traumatic Brain Injury

> **NIH NIH F31** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $46,036

## Abstract

PROJECT SUMMARY
Traumatic brain injury (TBI) is a leading cause of cognitive and motor impairment in the United States and is
estimated to result in long-term disability in approximately 1 to 2 percent of the population. Currently, all
pharmacological therapies focused on limiting neurodegeneration after TBI have been unsuccessful in
preventing secondary sequelae. Therefore, the prevention of secondary cognitive and motor sequelae is a
significant unmet need in neuroscience research.
Long myelinated axons within white matter are vulnerable to physical trauma and disruption of these tracts after
TBI results in white matter atrophy that is strongly correlated with both cognitive and motor dysfunction. Myelin
is generated by mature oligodendrocytes and is essential for robust propagation of action potentials and for the
survival and integrity of neuronal axons. Oligodendrocyte death and demyelination can therefore result in
increased vulnerability of axons, predisposing them to degeneration. Although progressive and chronic white
matter abnormalities are reported after TBI, the mechanisms initiated by mechanical strain on brain tissue that
contribute to oligodendrocyte dysfunction and white matter loss remain poorly defined. My preliminary data show
that multifactorial TBI induces dynamic changes in the oligodendrocyte lineage. With publicly available RNA
sequencing data I demonstrate that Yes-associated protein (YAP) may transcriptionally activate genes
upregulated in oligodendrocyte progenitor cells (OPCs) after TBI. YAP and its co-transcriptional activator PDZ-
binding motif (TAZ) are the nuclear effectors of the Hippo signaling pathway, a highly conserved pathway that
regulates organ growth and regeneration. Oligodendrocytes and OPCs are known to respond to mechanical
stimuli such as shear stress through the actions of YAP, however the consequences of YAP hyperactivity in this
lineage are unknown. I demonstrate that YAP hyperactivity is sufficient to impair OPC differentiation. The aims
of this proposal will seek to define 1) how modulation of YAP activity affects differentiation and proliferation of
OPCs and 2) whether YAP maintains the progenitor state in OPCs and unlocks a cryptic transcriptional program
when hyperactivated. These aims will be achieved using a combination stem cell biology and genomics
techniques, in conjunction with in vivo disease modeling. Understanding the functional consequences of YAP
activity in the oligodendrocyte lineage will offer new opportunities to prevent or reverse the neurological sequalae
of traumatic brain injury that affect millions of Americans.

## Key facts

- **NIH application ID:** 10314368
- **Project number:** 1F31NS124282-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Erin Frances Cohn
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314368

## Citation

> US National Institutes of Health, RePORTER application 10314368, Pathological Mechanotransduction by Oligodendrocytes After Traumatic Brain Injury (1F31NS124282-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10314368. Licensed CC0.

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