# Gene Expression Regulatory Pathways and Retinal Ganglion Cell Neuroprotection

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $501,447

## Abstract

Loss of retinal ganglion cells (RGCs) in glaucoma and traumatic and other optic neuropathies results in
permanent partial or complete blindness. Molecular mechanisms that may oppose this RGC death remain an
area of active investigation and potential high impact, as bridging RGC survival in chronic optic neuropathies
has high potential to preserve or restore vision. Multiple signal transduction pathways have been implicated
in RGC neuroprotection, including cAMP and neurotrophic factor-induced mitogen-activated protein kinase
(MAPK) signaling pathways. How these pathways synergistically promote RGC survival and elicit their
downstream effects remains unknown. Recent data from our labs support a model in which signalosomes
organized by the perinuclear scaffold protein muscle A-Kinase Anchoring Protein α (mAKAPα/AKAP6α)
mediate cAMP-dependent signaling and potentiate neuroprotective MAPK signaling, resulting in Ets
Like-1 protein (Elk-1) transcription factor activation and RGC survival. The identification of this intracellular
cAMP signaling compartment specifically relevant to neuroprotection provides a mechanism for spatially distinct
cAMP action and should inform the design of strategies providing therapeutic specificity greater than global
cAMP elevation with adenylyl cyclase activators or cAMP analogs. In this application, we propose three Specific
Aims to test this model and to elucidate the mechanism conferring the synergy between cAMP and neurotrophic
factor signaling in neuroprotection. Specific Aim 1: Defining Neuroprotective Gene Expression. Using single-
cell RNA transcriptome sequencing (scRNA-seq), we will study to what degree similar gene transcription
programs are induced by different neuroprotective interventions, including generalized versus
compartmentalized cAMP elevation, determine whether individual RGC subtypes are preferentially regulated by
cAMP and neurotrophic factor signaling, and identify gene candidates whose altered expression may be critical
for neuroprotection in response to therapeutic intervention. Specific Aim 2: Role of Perinuclear
Compartmented cAMP Signaling in RGC Neuroprotection. Using new tools to promote or inhibit cAMP and
Ca2+ in special intracellular compartments, we will test whether Ca2+-cAMP signaling at RGC mAKAPα
signalosomes is uniquely sufficient and/or necessary for RGC neuroprotection after optic nerve crush. Specific
Aim 3: Crosstalk Between cAMP- and Neurotrophic Factor-Dependent RGC Neuroprotection. To test
whether cAMP and neurotrophic factors promote neuroprotection through co-regulation of ERK1/2-dependent
Elk-1 activation, mice with gain- and loss-of-function for Elk-1 in RGCs will be subjected to optic nerve crush and
compared for their response to additional treatment with exogenous neurotrophic factors and AAV-mediated
mAKAPα signaling compartment enhancement. Together, these Specific Aims will provide molecular insights
into the signaling pathways and the altered gene expression that ...

## Key facts

- **NIH application ID:** 10530683
- **Project number:** 5R01EY032416-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jeffrey L Goldberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $501,447
- **Award type:** 5
- **Project period:** 2021-02-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10530683

## Citation

> US National Institutes of Health, RePORTER application 10530683, Gene Expression Regulatory Pathways and Retinal Ganglion Cell Neuroprotection (5R01EY032416-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10530683. Licensed CC0.

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