# Epigenetic pathways and cell cycle exit

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $360,725

## Abstract

PROPOSAL SUMMARY
Medulloblastoma is the most common pediatric brain tumor. Although some forms of medulloblastoma are
treatable by surgery and chemotherapy, others are resistant to the standard of care. In addition, behavioral
and cognitive deficits plague many medulloblastoma patients. Therefore, new therapeutic options are needed
for treating medulloblastoma. Inhibitors of the epigenetic reader protein Brd4 are currently being tried in
medulloblastoma patients due to their potential ability to reduce drivers of medulloblastoma growth including
MYC. However, the underlying biology of Brd4 in the developing brain is not understood. We have recently
shown that Brd4 knockout during development leads to cerebellar ataxia. We also demonstrated that Brd4
regulation via phosphorylation occurs during cell cycle exit of cerebellar granule cell progenitors. However,
the functional importance of this regulation is unclear. In the proposed studies we will determine whether Brd4
phosphorylation is part of a switch-like mechanism controlling cell proliferation and cell cycle exit in GCPs and
whether dysregulation of this process contributes to medulloblastoma. In Aim 1, we will determine the Brd4
signaling pathways important for GCP cell cycle exit. In Aim 2 we will determine the role of two upstream
kinases CK1d and CK2a in controlling Brd4 activity and cell cycle exit. In Aim 3, we will determine the
consequence of modulating Brd4 levels and phosphorylation status on progression of mouse medulloblastoma.
Collectively, these studies will reveal the importance of the epigenetic reader protein Brd4 in the decision to
proliferate or exit the cell cycle, which is critical for regulated development.

## Key facts

- **NIH application ID:** 10031091
- **Project number:** 1R01NS118023-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** NAGI G AYAD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,725
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10031091

## Citation

> US National Institutes of Health, RePORTER application 10031091, Epigenetic pathways and cell cycle exit (1R01NS118023-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10031091. Licensed CC0.

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