# Master epigenetic regulators and retinal degenerative disease

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $345,437

## Abstract

Project summary
Retinitis pigmentosa (RP) is the leading cause of inherited blindness afflicting one in every 3500 people. There
are no effective treatments for RP, and no prospects for a cure either as it is not yet practical to individually
correct the >2000 mutations (spread in ~70 genes) that initiate photoreceptor death. On the other hand, a com-
mon microglia-mediated pathogenic process has been recently identified among RP models and patients with
diverse mutations. Retinal microglia transform into an inflammatory state preceding rod degeneration. These
activated microglia decimate rods in a positive feedback loop thereby amplifying secondary cone loss. As mi-
croglial inflammatory activation is an early and common pathogenic event detrimental to rods, blocking it
should attenuate rod degeneration thereby preserving cones and day vision in RP patients. Our long-term goal
is to identify a master molecular switch governing the retinal microglial transition into the inflammatory state, so
as to establish a novel interventional target for broadly treating RP regardless of the genetic cause. We have
made an exciting preliminary finding that the Bromo and Extra-Terminal (BET) family of proteins may represent
such a novel target. Our central hypothesis is that the BET family is a master epigenetic switch, inhibition of
which blocks the microglial inflammatory transition and protects photoreceptor survival. We were the first to
report that blocking the entire BET family abrogates retinal microglial inflammation and mitigates photoreceptor
loss in the rd10 mouse model of RP. BET proteins each contains two acetyl-histone binding bromodomains
that can be pharmacologically blocked. Upon pathogenic stimulation, BET proteins assemble with key tran-
scription factors at, and co-activate the expression of, a select set of pathogenic genes in a cell state-specific
manner. To investigate the BET regulatory mechanism governing the resting-to-inflammatory state transition of
microglia, we will delineate which BET protein(s) dictate microglial inflammation (Aim-1), and define the bromo-
domain(s) responsible for this BET function (Aim-2) as well as the BET-associated key transcription fac-
tor(s)(Aim-3). This proposal is innovative considering that the BET family is not merely another redundant
downstream pathway. Rather, it is an upstream epigenetic determinant of pathogenic cell state transition.
Thus, BET targeting should logically lead to more effective inhibition of microglial inflammation and protection
of photoreceptors. This project will ultimately lead to a new paradigm of epigenetically targeted “epi-drug ther-
apy” to effectively mitigate RP without having to genetically target individual mutations and downstream path-
ways. As microglial inflammation is a hallmark of retinal degenerative diseases, this research will have a broad
impact on millions of patients with conditions beyond RP.

## Key facts

- **NIH application ID:** 10306197
- **Project number:** 7R01EY029809-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Lianwang Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,437
- **Award type:** 7
- **Project period:** 2021-01-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306197

## Citation

> US National Institutes of Health, RePORTER application 10306197, Master epigenetic regulators and retinal degenerative disease (7R01EY029809-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10306197. Licensed CC0.

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