# Regulation of Glia-driven Neuroinflammation in Glaucoma

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $388,000

## Abstract

PROJECT SUMMARY
 Recent studies of clinical/postmortem and experimental samples have accumulated evidence that supports a
connection of inflammatory responses to neurodegeneration in glaucoma. Although inflammatory aspects of
glaucomatous neurodegeneration are attracting increasing attention, how neuroinflammation is regulated in
glaucoma, and how we can prevent neurodegenerative inflammation remain unknown. Here, we present
experimental data leading us to hypothesize that NF-κB plays a key role in activating the glia-driven
neuroinflammation in the glaucomatous retina and optic nerve, and that targeting this transcriptional activator
mechanism is a logical strategy to provide immunomodulation and avoid secondary injury processes. With respect
to intimate inter-relationship between astroglia and microglia in induction of the inflammatory/neurotoxic
phenotype, NF-κB, the key transcriptional activator of inflammatory mediators, should be critical for both glial
subtypes and their interaction in neuroinflammation in glaucoma. To test this hypothesis, we will comparatively
study glial subtype-targeted conditional transgenic lines (in which the NF-κB canonical pathway is inactivated by
drug-induced deletion of IκKβ in astroglia or microglia) and background controls with or without ocular
hypertension (induced by anterior chamber microbead/viscoelastic injections). We will longitudinally analyze glial
subtype-targeted transgenic effects on a diverse set of inflammatory outcomes at different sites of injury (retina,
optic nerve head, and optic nerve axons). The studied outcomes will include the glial inflammatory activation
phenotype and cell type-specific effects of glial subtype-targeted IκKβ deletion. Besides a preselected set of
molecules, freshly isolated samples of astroglia and microglia will be analyzed by quantitative mass spectrometry
to also gain high-throughput molecular information about transgenic effects on NF-κB-regulated inflammation
pathways, other transcriptional targets of NF-κB, and molecules relevant to glial neurosupport functions. Since glia
drive both innate and adaptive immune responses in glaucoma, additional analysis will include T-cell reactivity
and autoantibody production. To determine whether transgenic inhibition of glial NF-κB (and neuroinflammation)
protects neurons from immunogenic injury in mouse glaucoma, we will also analyze neuron structure (by RGC
and axon counts) and function (by PERG). We expect that this project, complementing the astroglia- or microglia-
targeted transgenic lines with molecular analysis of astroglia-specific and microglia-specific responses (in isolated
cell type-specific samples) will allow us to determine the role of NF-κB in individual contribution and inter-
relationship of astroglia and microglia in neuroinflammation (in the retina, optic nerve head, and axons),
characterize specific molecular components, and value glial NF-κB as a treatment target to restore immune
homeostasis and provi...

## Key facts

- **NIH application ID:** 10168546
- **Project number:** 5R01EY028153-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Gulgun TEZEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,000
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168546

## Citation

> US National Institutes of Health, RePORTER application 10168546, Regulation of Glia-driven Neuroinflammation in Glaucoma (5R01EY028153-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10168546. Licensed CC0.

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