# Identification of novel phosphodiesterase (PDE)-modulating compounds and characterization of associated cytoprotective pathways in lightdamagedretina

> **NIH NIH F30** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $51,752

## Abstract

PROJECT SUMMARY
Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes ubiquitously expressed in the human body,
and they play a critical role in a broad range of physiological processes, including regulation of the immune
system, cardiovascular function, metabolism, reproduction, neurobiological processes of learning and memory,
and vision. PDEs function enzymatically to hydrolyze intracellular cyclic nucleotide second messengers (cAMP
and cGMP), thereby affecting various downstream cellular signaling pathways that control homeostatic
processes. These include repair mechanisms that promote cell survival (somatic maintenance), as well as pro-
apoptotic mechanisms that result in cell death. In aging and disease, dysregulation of these signaling networks
can lead to a reduced investment in somatic maintenance, resulting in pathophysiological states of disease.
However, as key regulatory nodes that modulate intracellular and subcellular concentrations of second
messenger signaling molecules, it is conceivable that PDEs could be pharmacologically targeted in order to
upregulate pathways that improve cellular viability in disease states. By integrating recent advances in PDE
biology with high-throughput methods, this proposal aims to identify new PDE-targeting agents and further
characterize the pathways through which they alleviate pathophysiology in chronic, debilitating disease.
Specifically, our focus will be on the application of newly identified therapeutic agents to ameliorating disease in
a mouse model of retinal degeneration. Our long-term goal is to obtain a better understanding of the role played
by PDE-dependent signaling pathways in the pathogenesis of retinal degeneration and to develop interventions
that stop the progression of human blinding diseases.
Accordingly, we propose three thematically and experimentally linked Specific Aims, to: 1) identify novel PDE-
modulating compounds through in silico screening, 2) evaluate the therapeutic efficacy of PDE-selective
inhibitors in preventing retinal degeneration, and 3) validate a systems pharmacology approach to optimizing
PDE inhibitor therapy. Successful completion of Aim 1 will result in the discovery of novel compounds that
circumvent the limitations of existing PDE inhibitors and exhibit superior targeting selectivity with enhanced
potential for clinical utility. Through completion of Aim 2, we intend to demonstrate a statistically significant
therapeutic effect conferred by PDE inhibition that is robustly conserved across different mouse models of retinal
degeneration. Lastly, successful completion of Aim 3 will dissect the underlying molecular mechanisms of
cytoprotection in the context of stress-induced retinal degeneration, thereby providing innovative systems biology
insights on the synergism between intersecting networks involving crosstalk among the many different cell types
in the retina. Indeed, these insights will facilitate a more unified perspective to attain o...

## Key facts

- **NIH application ID:** 10418610
- **Project number:** 5F30EY031566-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Jennings C Luu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418610

## Citation

> US National Institutes of Health, RePORTER application 10418610, Identification of novel phosphodiesterase (PDE)-modulating compounds and characterization of associated cytoprotective pathways in lightdamagedretina (5F30EY031566-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10418610. Licensed CC0.

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