# Gene Expression Regulatory Pathways and Retinal Ganglion Cell Neuroprotection

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $55,138

## 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. Identifying 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 therapeutics 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
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 can confer ...

## Key facts

- **NIH application ID:** 10611728
- **Project number:** 3R01EY032416-02S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jeffrey L Goldberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $55,138
- **Award type:** 3
- **Project period:** 2022-07-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10611728

## Citation

> US National Institutes of Health, RePORTER application 10611728, Gene Expression Regulatory Pathways and Retinal Ganglion Cell Neuroprotection (3R01EY032416-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10611728. Licensed CC0.

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