# Development and application of chemical timers for precise control of protein abundance in the eye

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $246,000

## Abstract

Project Summary
The ability to spatially and temporally control cellular signaling is a fundamental requirement of organismal and
tissue development/function. As an organ, the eye is not exempt from these requirements. In fact, arguably, the
retina is even more sensitive than other tissues to environmental or genetic disturbances which can affect the
transduction of light into electrochemical potential that is ultimately recognized by the brain. Thus, unregulated
gene expression (also called phenotoxicity) during inappropriate times (temporally agnostic), or pan-retina
activation/repression of cellular signaling using small molecules regardless of cell type (spatially agnostic), have
the potential to compromise physiologic signaling with dire consequences. To circumvent these potential adverse
consequences, and to develop an idealized gene-therapy platform, we have thoroughly validated and utilized a
chemical biology approach involving destabilizing domains (DDs) in the mouse retina. These DD tools allow for
conditional control of protein abundance through the addition of an exogenously-added small molecule stabilizer
(typically trimethoprim, TMP, for the E. coli dihydrofolate reductase [DHFR] domain) and can achieve temporal
control on near physiologically-relevant timescales within the retina. We envision that such approaches will
provide idealized therapeutics that can target desired cell types affected in disease and according to defined
timeframes. The overall goal of this R21 is to substantially expand the novelty, capability, and applicability of
available small molecule probes that can be used in vivo for conditionally regulating retinal stress responsive
signaling using DDs. This work is important because it will significantly enable the scientific community to
interrogate retinal biologic phenomena with increasing spatio-temporal precision and flexibility, and it will test the
ideological boundaries and therapeutic utility of conditional gene therapies.

## Key facts

- **NIH application ID:** 10354805
- **Project number:** 1R21EY033522-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** John Douglas Hulleman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $246,000
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354805

## Citation

> US National Institutes of Health, RePORTER application 10354805, Development and application of chemical timers for precise control of protein abundance in the eye (1R21EY033522-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10354805. Licensed CC0.

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