# Regulating Inosine 5'-Monophosphate Dehydrogenase in Healthy and Diseased Photoreceptor Cells

> **NIH GM P20** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2026 · $257,400

## Abstract

PROJECT SUMMARY
Patients with retinitis pigmentosa (RP) due a mutation in inosine monophosphate dehydrogenase 1 (IMPDH1) expe-
rience an early onset and debilitating retinal degeneration that leads to blindness. IMPDH1, a critical enzyme in the
de novo synthesis of guanine nucleotides, places it at the nexus of cellular homeostasis. While guanine nucleo-
tides are universally indispensable, mutations in IMPDH1 primarily manifest in retinal degeneration, emphasizing
the unique vulnerability of the retina to IMPDH1 dysregulation. While IMPDH1's central role in nucleotide biosyn-
thesis is well established, the nuanced regulatory mechanisms dictating its activity in the human retina are un-
known. Preliminary investigations have revealed a link between IMPDH1 and MOK kinase (MAPK/MAK/MRK
Overlapping Kinase), a member of the RCK (ros-cross hybridizing kinases) family known for its role in cilium
length regulation. Given the established involvement of RCK kinases in cilium length regulation, it is reasonable
to postulate that MOK kinase may play a crucial role in modulating photoreceptor outer segments. Our hypoth-
esis is that IMPDH1 is negatively regulated by MOK kinase and that mutations associated with RP disrupt the
interaction between these enzymes leading to decreased feedback inhibition and accumulation of toxic levels of
guanine nucleotides. Specific Aim 1 will test the hypothesis that MOK kinase increases IMPDH1 sensitivity to
GTP feedback inhibition in human photoreceptor cells and that this sensitivity is lost with the IMPDH1 D311N
mutation. We will use patient-derived retinal organoids to model the human retina to determine the effect of MOK
kinase on IMPDH1 enzyme kinetics. We will compare IMPDH1 enzyme activity in MOK-knock out (KO) retinal
organoids expressing wild type (WT) IMPDH1 or the common RP mutation D311N. Specific Aim 2 will test the
hypothesis that guanine nucleotide pools increase IMPDH1 interactions with MOK kinase and that mutations in
IMPDH1

## Key facts

- **NIH application ID:** 11267910
- **Project number:** 1P20GM161969-01
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Lea D Bennett
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** GM
- **Fiscal year:** 2026
- **Award amount:** $257,400
- **Award type:** 1
- **Project period:** 2026-05-01T00:00:00 → 2031-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11267910

## Citation

> US National Institutes of Health, RePORTER application 11267910, Regulating Inosine 5'-Monophosphate Dehydrogenase in Healthy and Diseased Photoreceptor Cells (1P20GM161969-01). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/11267910. Licensed CC0.

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