Department of Ophthalmology and Vision Science

Case Western Reserve University

Cleveland, OH

BASIC RESEARCH PROJECT

The impact of BRD4 on the development of diabetic retinopathy

Research Interests

BRD4 is an epigenetic regulator that enhances inflammation and oxidative stress. Recently, Dr. Taylor discovered that BRD4 is upregulated in the human retina and blood of diabetics with retinopathy. Levels of BRD4 correlates to the severity of diabetic retinopathy. Landmark clinical studies of glycemic control and diabetic complications provide strong evidence that glycemic variability elicits a “metabolic memory” that impacts the development of diabetic retinopathy. It was later discovered that metabolic memory is initiated by diabetes-mediated epigenetic modifications; such as, histone acetylations throughout the retina. These epigenetic modifications mediate proinflammatory gene transcription, which leads to retinal inflammation, oxidative stress, and the onset of diabetic retinopathy. BRD4 is an epigenetic regulator that can initiate proinflammatory gene transcription when it binds to acetylated histones. This is of interest because it has been reported that BRD4 enhances inflammation, oxidative stress, and the progression of other diabetic complications and ocular diseases. Per the literature and our preliminary findings, we postulate that BRD4 is the intercedent between metabolic memory and retinal pathogenesis. Thus, the overall goal of this study is to determine if BRD4 is a compelling therapeutic target that can halt the onset of diabetic retinopathy.

Plans for 2025

Through this study, Dr. Taylor will provide a full understanding of the functional impact of BRD4 on vascular and neuroretina damage. Subsequently, her team will determine if a BRD4 inhibitor (MS436) has the therapeutic efficacy to halt the development of diabetic retinopathy in mice. Dr. Taylor is optimistic that a novel therapeutic target for diabetic retinopathy will be discovered during this study. This type of translational discovery would be highly impactful to millions of diabetics that suffer from this blinding disease.

Dr. Taylor’s lab team postulates that BRD4 inhibition will halt retinal damage, vision loss, and diabetes-mediated metabolic memory that initiates the onset of retinopathy.

Successful completion of this project will define the impact of BRD4 throughout the development of diabetic retinopathy. This will broaden our understanding of mechanisms inherent to the onset of retinal pathogenesis, while also potentially leading to the discovery of a therapeutic target for the progression of diabetic retinopathy.

Type of Project: Basic/Translational Research