# Biochemical mechanisms of beta cell protection through bromodomain inhibition

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $390,000

## Abstract

PROJECT SUMMARY
Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency resulting from reduced
function and progressive loss of insulin-producing pancreatic β-cells. Although many T-cell-dependent
mechanisms underlie T1D progression, the role of the β-cell responses in promoting autoimmune inflammation
is poorly understood. Our long-range goals are to determine the role of the three ubiquitously expressed
bromodomain and extraterminal (BET) family members (BRD2/3/4) in β-cell transcriptional responses to
inflammation associated with autoimmune diabetes. Each BET protein contains two bromodomains, which are
epigenetic ‘readers’ of lysine acetylation on histones and transcription factors, and bromodomain binding to
acetylated histones/proteins regulates transcription in a gene- and cell-type dependent manner. Interestingly,
pan inhibitors that equally target both bromodomains of all BET proteins elicit broad anti-inflammatory effects
and delay diabetes onset in the non-obese diabetic T1D mouse model. However, the direct effects of BET
bromodomain inhibitors on the function and viability of β-cells are largely unknown. We hypothesize that β-cell
inflammation (Aim 1) and identity (Aim 2) can be regulated by selectively inhibiting BET proteins in a
bromodomain- and cell-type-specific manner. Broad inhibition of all BET bromodomains and the inability to
directly target specific cell types are significant challenges, and such broad inhibition is associated with dose-
limiting toxicities and adverse effects. We will address these limitations by evaluating the transcriptional actions
of next-generation BET bromodomain inhibitors that are selective for a subset of BET bromodomains (Aim 1
and 2) and develop innovative methods to selectively target BET bromodomain inhibitors to β cells (Aim 3).
Completing these aims will uncover the precise gene- and cell-type-specific mechanisms by which BET
bromodomain inhibition modulates β-cell transcription, inform the development of next-generation β-cell
targeted inhibitors, and advance T1D treatment and β-cell replacement strategies.

## Key facts

- **NIH application ID:** 10880990
- **Project number:** 2R01DK119359-06
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Brian Christopher Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 2
- **Project period:** 2018-09-20 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880990

## Citation

> US National Institutes of Health, RePORTER application 10880990, Biochemical mechanisms of beta cell protection through bromodomain inhibition (2R01DK119359-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10880990. Licensed CC0.

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