# Discover the signaling basis for OPC homeostasis

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2022 · $453,110

## Abstract

In this proposal, we will address a fundamentally important problem in glia biology: how do oligodendrocyte
precursor cells (OPCs) robustly maintain their numbers? Previous intravital imaging experiments demonstrated
that OPCs exert mutual inhibition when they contact each other, but promptly enter cell cycle when neighboring
OPCs either differentiate or die, and halt proliferation again when homeostasis is achieved. However, the
molecular basis behind OPC homeostasis remains largely unknown. Recently, using a mouse genetic system
called Mosaic Analysis of Double Markers (MADM) to model glioma, our lab discovered that OPC is a cell of
origin for glioma, and revealed that, instead of passively over-expanding, mutant OPCs actually outcompete
WT OPCs and eventually take over the entire brain. Most importantly, when we genetically blocked cell
competition of mutant OPCs, glioma can be completely prevented. Putting the observations of OPC
homeostasis in health and OPC competition in gliomagenesis together, we realized that these are the two
sides of the same coin, and that there is a Yin/Yang mechanism for OPC proliferation that counterbalances
each other in health but gets deregulated in cancer. While the Yang network of RTK signaling is well studied,
the Yin network is much less understood, let alone their counter-interactions. Here, we hypothesize that
phospho-proteomic/proteomic profiling and subsequent candidate validation using highly sensitive OPC
competition platforms should enable us to provide mechanistic insights into this Yin/Yang network. To test this
hypothesis, we have assembled a team of experts on OPC purification and culture, proteomic profiling with
limited materials, and using advanced statistical and unsupervised learning approaches to predict signaling
network based on phospho-proteomic/proteomic profiles. As a team, we have successfully performed a pilot
experiment that led to a handful of candidate genes. In Aim 1 of this proposal, we will validate the role of these
candidate genes in OPC competition. In Aim 2 of this proposal, we will perform further in-depth profiling
experiments to gain a comprehensive insight into the signaling network that controls OPC homeostasis and
competition. The findings from our project should motivate further functional studies to clearly delineate the
entire pathway, deepen our understanding of OPC homeostasis, and shed light on paradigm-shifting
therapeutic strategies for glioma based on the concept of OPC competition.

## Key facts

- **NIH application ID:** 10525872
- **Project number:** 1R21NS125479-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Hui Zong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,110
- **Award type:** 1
- **Project period:** 2022-08-09 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525872

## Citation

> US National Institutes of Health, RePORTER application 10525872, Discover the signaling basis for OPC homeostasis (1R21NS125479-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10525872. Licensed CC0.

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