# Targeting NAD metabolism to ameliorate bacterial endophthalmitis

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2022 · $368,848

## Abstract

Project Summary
Bacterial endophthalmitis is a vision-threatening complication commonly occurring post penetrating eye injuries
and ocular surgeries. Despite aggressive antibiotics and surgical interventions, endophthalmitis often results in
partial or complete vision loss. The long-term goal of our research has been to study the pathobiology of
endophthalmitis and identify potential therapeutic targets for treatment. In our recent study (PMID: 34095879),
using transcriptomics and untargeted metabolomics, we identified several key pathways related to energy
metabolism being perturbed during Staphylococcus aureus (SA) endophthalmitis. Among these pathways, we
found that bacterial infection rapidly depletes the nicotinamide adenine dinucleotide (NAD+) pool in the mouse
retina. NAD+ is not only crucial for oxidation-reduction reactions in the mitochondria, but metabolites of the NAD+
pathway also serve as substrates for various enzymes (e.g., PARPs, sirtuins, and CD38) to maintain cellular
homeostasis. Thus, dysregulation in NAD+ metabolism has emerged as a contributing factor in the pathogenesis
of several diseases. However, its role has not been investigated in ocular infections. Here, we propose that NAD+
depletion causes bioenergetics collapse, leading to the activation of receptor-interacting protein kinase-3
(RIPK3) mediated retinal cell death. In support, our preliminary data show disruption of the NAD+ synthesis via
salvage pathway, increased activity of CD38 NADase, and the activation of RIPK3/MLKL signaling in SA-infected
retina and cultured cells. Using a combination of mouse genetic tools, gene therapy, and pharmacological
interventions, we will determine mechanisms of NAD+ depletion and restoration of salvage pathway (Aim 1),
elucidate the crosstalk between CD38 NADase activity and RIPK3 in regulating retinal cell death (Aim 2), and
test the hypothesis whether supplementation of NAD+ precursors can be used as an adjunct therapy to treat
bacterial endophthalmitis (Aim 3). Collectively, the mechanistic insights on NAD+ dysregulation and NAD+
supplementation treatment strategies developed in this proposal could have a major impact in the field, not only
with regards to ocular infections but other systemic infectious diseases as well.

## Key facts

- **NIH application ID:** 10445516
- **Project number:** 2R01EY026964-06
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Ashok Kumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,848
- **Award type:** 2
- **Project period:** 2017-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445516

## Citation

> US National Institutes of Health, RePORTER application 10445516, Targeting NAD metabolism to ameliorate bacterial endophthalmitis (2R01EY026964-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10445516. Licensed CC0.

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