# IMPDH1 structure and function in the healthy and diseased retina

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2020 · $40,870

## Abstract

Project Summary/Abstract
 Inherited retinal degeneration in humans is an incurable disease that causes blindness. A variety of genes
and mutations in both coding and non-coding regions have been associated with retinal degeneration but little is
known about the molecular mechanism of disease. This proposal focuses on the highly-conserved enzyme IMP
dehydrogenase 1 (IMPDH1), a key regulatory enzyme in purine biosynthesis. Nine different missense mutations
in IMPDH1 have been identified in humans that lead to retinal degeneration in the form of autosomal dominant
retinitis pigmentosa, with varying degrees of severity and age of onset. None of the mutations has a direct effect
on enzyme activity or results in a disease phenotype in any tissue other than the retina. The lack of direct
enzymatic affect or an animal model to study IMPDH1 retinal degeneration has stalled progress towards
determining the mechanism of disease.
 IMPDH forms microns-long dynamic filamentous structures in vitro and in vivo in response to changing
metabolic conditions. The physiological conditions that promote assembly/disassembly and cellular function of
the filaments remain unclear. I have discovered that IMPDH1 retinal disease mutations have a direct effect on
the ability of the enzyme to polymerize, either preventing polymerization entirely or promoting hyper-assembly.
 Here, I propose a collaborative and multidisciplinary approach to combine high resolution cryo-EM with the
development of the first animal model to study IMPDH1-associated retinal degeneration. This effort will provide
novel insight into the role of IMPDH1 in photoreceptors and lay the groundwork for future therapies to prevent
blindness due to cell death. This varied and ambitious proposal builds off my own training in cryo-EM and
provides the opportunity for me to gain experience working with a model organism and utilizing different imaging
techniques. In addition to becoming an expert cryo-EM user and gaining experience working with a model
organism, my fellowship training plan focuses on seeking out opportunities to present this research and hone
my science communication skills. The experience gained from the proposal will set me on the track for a
productive postdoc and ultimately running my own independent lab.
Hypothesis: IMPDH1 retinal degeneration mutations affect the ability of the enzyme to form ultrastructures
which leads to a dysregulation of the enzyme, resulting in disruption of nucleotide homeostasis and eventually
cell death.
Aim 1: Determine IMPDH1 filament structure and function in vitro and localization in the retina.
Aim 2: Define biochemical and physiological consequences of IMPDH1 retinopathy mutants

## Key facts

- **NIH application ID:** 10020180
- **Project number:** 5F31EY030732-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Anika Lauren Burrell
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,870
- **Award type:** 5
- **Project period:** 2019-09-16 → 2022-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020180

## Citation

> US National Institutes of Health, RePORTER application 10020180, IMPDH1 structure and function in the healthy and diseased retina (5F31EY030732-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10020180. Licensed CC0.

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