# CaMKII: Retinal Ganglion Cell Neuroprotection and Axon Regeneration

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $555,582

## Abstract

Expression of activated forms of the multifunctional type II Ca2+/calmodulin-dependent protein kinase (CaMKII)
were recently demonstrated to confer robust retinal ganglion cell (RGC) neuroprotection in mouse models of
optic nerve injury and NMDA excitotoxicity, making CaMKII a leading target for therapeutic intervention in
glaucoma. However, new preliminary data show that expression of constitutively active CaMKII (caCaMKII) not
only promotes RGC survival after optic nerve crush (ONC) injury, but also suppresses axon regeneration. As
axon regeneration will be a necessary feature of any potential treatment for glaucoma that would restore
vision, a better understanding of the mechanisms how caCaMKII confers neuroprotection will be important for
the successful development of CaMKII-directed therapeutics. We hypothesize that the phosphorylated
effectors driving CaMKII-dependent neuroprotection and axon growth repression are different. In this
project, we will derive strategies that promote RGC survival, but not prevent axon regeneration by investigating
how differential compartmentation and activation confer CaMKII phosphorylation of relevant effectors and their
respective cellular processes. In particular, we hypothesize that induction of CREB and/or NF-κB gene
expression by nuclear CaMKII and potentially CaMKIV is required for RGC survival, while as an off-target
effect, caCaMKII expression elsewhere in the cell suppresses axon growth. Specific Aim 1: The role of
endogenous CaMKII in RGC neuroprotection and axon suppression. In this Aim, we will use knock-out
mice to test whether endogenous CaMKII and CaMKIV expression is required for maintenance of basal RGC
survival or for neuroprotection after ONC. In addition, we will test whether CaMKII knock-out will promote axon
regeneration. By AAV-mediated expression of CaMKII-activating peptides, we will differentiate between
alternative mechanisms for caCaMKII’s neuroprotective effects: replacement of insufficiently expressed
CaMKII or activation of insufficiently active endogenous CaMKII. In parallel to assay for neuroprotection, we
will study the activity of CaMKII in vivo by transpupillary imaging of a CaMKII fluorescent reporter. Specific
Aim 2: Compartment-specific caCaMKII neuroprotection and suppression of axon regeneration. We will
test whether exogenously expressed caCaMKIIα fusion proteins localized to different intracellular domains
selectively promote neuroprotection or suppress axon regeneration after optic nerve injury. Conversely, we will
test whether localized expression of CaMKII inhibitory peptides will rescue caCaMKII-suppressed axon
regeneration without inhibiting neuroprotection. Specific Aim 3: CaMKII-dependent RGC gene expression
conferring neuroprotection. We hypothesize that activation of CaMKII signaling confers neuroprotection by
induction of CREB- and NF-κB-dependent gene expression. scRNA-seq and scATAC-Seq will be used to
identify genes and regulatory elements associated wit...

## Key facts

- **NIH application ID:** 10855938
- **Project number:** 1R01EY036028-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jeffrey L Goldberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $555,582
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855938

## Citation

> US National Institutes of Health, RePORTER application 10855938, CaMKII: Retinal Ganglion Cell Neuroprotection and Axon Regeneration (1R01EY036028-01). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/10855938. Licensed CC0.

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