# Degrading BET Proteins is Neuroprotective in Ischemic Stroke

> **NIH NIH F31** · UNIVERSITY OF FLORIDA · 2020 · $32,527

## Abstract

PROJECT DESCRIPTION
Neuroinflammation after stroke significantly contributes to neuronal cell death. Bromodomain and Extra
Terminal Domain (BET) proteins are essential to inflammatory gene transcription. There are four BET proteins:
BRD2, BRD3, BRD4, and BRDT. BRD2 and BRD4 are abundant and ubiquitously expressed. BRD3
expression is very low in most tissues including the brain, and BRDT is testis specific. BET proteins contain
two conserved bromodomains that associate with acetylated lysines, and an extraterminal domain. BET
proteins have varied effects including chromatin remodeling, histone acetyltransferase activity, and as
scaffolds to recruit transcription factors; they couple chromatin remodeling with transcription. We hypothesize
that BET blockade will provide a multipronged approach to reducing cell death after stroke. BRD2 normally
represses peroxisome proliferator activator γ (PPARγ) activity, which has an anti-inflammatory effect, so we
expect that inhibiting BRD2 will increase anti-inflammatory gene transcription. BRD2 knockdown also
decreases nuclear factor-κB (NF-κB) activation, which is a major regulator of pro-inflammatory gene
transcription in stroke. BRD4 acts as an NF-κB co-activator, therefore we predict that BRD2 and BRD4
inhibition will decrease pro-inflammatory gene transcription in the ischemic brain. Furthermore, because BRD2
and BRD4 constitutively inhibit nuclear factor (erythroid-derived 2)-related factor (Nrf2) which is essential to
antioxidant gene transcription, we expect BRD2/4 inhibition to increase expression of antioxidant genes,
reducing oxidative stress. Little is known regarding the role of BET proteins in stroke, but our preliminary data
shows that BET inhibition reduces infarct in a rodent model of stroke. Our long-term goal is to reduce the
spread of stroke damage by limiting the effects of secondary inflammation. Our hypothesis is that BET
inhibition is neuroprotective in ischemic stroke by limiting the deleterious effects of secondary inflammation.
Our main objective is to determine the mechanism by which BET inhibition is protective in ischemic stroke. In
Aim 1, we will determine the neuroprotective effect of BET blockade after ischemia using dBET1 (a proteolysis-
targeting chimera that degrades BET proteins). We will utilize male mice subjected to ischemic stroke to
investigate the effects of BET blockade on infarct size and long-term behavioral outcomes. In Aim 2, we will
determine the effects of BET blockade on stroke-induced neuroinflammation. This project will provide
mechanistic insights into how BET proteins contribute to secondary injury after ischemic stroke. These data will
yield a positive impact as it will provide a strong foundation for future development of novel therapeutic
strategies targeting BET proteins to reduce stroke damage.

## Key facts

- **NIH application ID:** 9906760
- **Project number:** 5F31NS111839-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Kelly M DeMars
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,527
- **Award type:** 5
- **Project period:** 2019-04-01 → 2020-12-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906760

## Citation

> US National Institutes of Health, RePORTER application 9906760, Degrading BET Proteins is Neuroprotective in Ischemic Stroke (5F31NS111839-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9906760. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*