# Redox Signaling in Neurofibromatosis

> **NIH NIH R01** · OREGON STATE UNIVERSITY · 2022 · $315,792

## Abstract

PROJECT SUMMARY
Neurofibromatosis type 2 (NF2) is a debilitating and medically-incurable tumor disorder of the nervous system
caused by inactivating mutations of the gene that encodes merlin tumor suppressor. NF2 patients develop
multiple schwannomas throughout the nervous system for which there is no pharmacological treatment.
Patients undergo debilitating repeated invasive surgeries to remove or debulk tumors growing along the
nerves, risking permanent nerve damage. Growing evidence implicates protein oxidation by reactive nitrogen
species as a major contributor to tumor growth, but the specific oxidative modifications and target proteins
that mediate tumorigenic activity are unknown. Our goals are to reveal novel mechanisms that mediate
dysregulation of cell proliferation in NF2 and identify specific oxidatively modified proteins that may serve as
tumor-directed, non-invasive therapeutic targets for NF2 and other tumors.
Our exciting preliminary findings revealed that one such oxidative modification, tyrosine (Tyr) nitration,
selectively supports schwannoma cell survival and contributes to schwannoma metabolic phenotype by
decreasing oxidative phosphorylation complex IV levels and activity, while increasing glycolysis and
glutaminolysis. Further, we identified 31 endogenous nitrated proteins in schwannomas, including Hsp90,
which we showed decreases mitochondrial respiration when nitrated, the transcription factor GABP,
responsible for the regulation of complex IV expression, and 5 tumorigenic proteins that participate in
signaling pathways that are deregulated in NF2. We will thus test the hypothesis that selective Tyr nitration of
proteins in NF2 dysregulates mitochondrial respiration and signaling pathways that are responsible for
metabolic reprogramming, which in turn supports proliferation and survival of schwannomas. Driven by
strong preliminary data we will elucidate the mechanism by which Tyr nitration regulates complex IV
expression and activity (Aim 1); and determine the specific nitrated proteins and mechanisms that promote
schwannoma metabolic reprogramming and growth (Aim 2).
The proposed research is highly innovative, because it will identify concept-advancing and exceptional novel
targets for drug development that are present in tumors but not in normal tissues. Furthermore, these findings
are of high significance to human disease, since they may pave the way to completely new and efficacious
treatment modalities, not only for NF2, but also for other solid tumors in the future.

## Key facts

- **NIH application ID:** 10352387
- **Project number:** 5R01NS102479-04
- **Recipient organization:** OREGON STATE UNIVERSITY
- **Principal Investigator:** Maria Clara Franco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $315,792
- **Award type:** 5
- **Project period:** 2019-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352387

## Citation

> US National Institutes of Health, RePORTER application 10352387, Redox Signaling in Neurofibromatosis (5R01NS102479-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10352387. Licensed CC0.

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