# Kinase Multitargeting for Glaucoma Neuroprotection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $395,000

## Abstract

PROJECT SUMMARY
Glaucoma is a neurodegenerative disease defined by the injury of retinal ganglion cell (RGC) axons at the optic nerve head,
leading to cell death and irreversible vision loss. Current therapies center around lowering intraocular pressure (IOP)
although this can be challenging in some patients. In order to advance towards a neuroprotective strategy that could
complement IOP-lowering, we have been identifying potential neuroprotective targets in primary RGCs using high-
throughput functional genomic screening. We initially identified dual leucine zipper kinase (DLK) and its paralog, leucine
zipper kinase (LZK) as being key upstream activators of JUN N-terminal kinase (JNK) and axon injury signaling. We
showed that DLK/LZK inhibition provides robust and durable protection to RGCs in multiple rodent models of optic
neuropathy and, more recently, validated the survival effect in a nonhuman primate model of glaucoma. Despite their
central role as neuronal messengers of axonal injury, little is known about the regulation of DLK/LZK. Moreover, inhibition
of DLK/LZK prevents axon regeneration and has only modest effects on distal axon degeneration. Using chemical genetic-
and clustered regularly interspaced short palindromic repeat (CRISPR)-based screens, we have identified two subgroups of
Sterile 20 (STE20) kinases, including thousand and one amino acid (TAO) and germinal center kinase IV (GCK-IV) kinases
which seem to regulate the interpretation and duration of the DLK/LZK axon injury signal. Moreover, inhibition increases
rather than decreases axon regeneration and has a much greater impact on distal axonal degeneration. Based on insights
from cancer biology, we recognized that similar STE20 kinases converge to regulate Hippo signaling, a developmental
growth pathway not previously linked to axon injury signaling. We show that inhibition of the central kinases of Hippo
signaling, large tumor suppressor (LATS) 1 and 2, robustly protects primary mouse RGCs and we attempt to demonstrate
that the canonical Hippo transcription factor, transcriptional coactivator with PDZ-binding motif (TAZ) modulates
DLK/LZK signaling by affecting JUN-dependent transcription. The central theme of this proposal is that combinatorial
inhibition of STE20 kinases can be leveraged to generate robust somal and axonal protection combined with long-distance,
sustained axon regeneration and that a key molecular mechanism involves Hippo signaling. In Specific Aim 1 (SA1), we
focus on the role of STE20 kinases in axon degeneration and evaluate the potential for pancellular and functional RGC
protection in a rat model of glaucoma. For this, we built a novel all-in-one adeno-associated virus (AAV)/CRISPR reagent
capable of disrupting multiple kinases. In SA2, we test the role of combinatorial STE20 kinase inhibition in axon
regeneration. We also use transcriptomic assays to dissect the mechanism by which DLK/LZK and STE20 kinase inhibition
differs with respect to axon r...

## Key facts

- **NIH application ID:** 10812168
- **Project number:** 2R01EY029342-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Derek Stuart Welsbie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,000
- **Award type:** 2
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812168

## Citation

> US National Institutes of Health, RePORTER application 10812168, Kinase Multitargeting for Glaucoma Neuroprotection (2R01EY029342-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10812168. Licensed CC0.

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