Gene Networks that Regulate Ganglion Cell Death and Axon Regeneration

Kimberly Wong, PhD Boston Children's Hospital


Larry Benowitz, PhD


This work aims to identify novel transcriptional mechanisms by which dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) regulate retinal ganglion cell (RGC) death and axon regenerative competence. I will use gene-editing techniques in a mouse optic nerve injury model to study DLK/LZK-dependent signaling mechanisms. By deleting downstream signaling effectors, I hope to identify DLK/LZK-dependent genes that can block neurodegeneration without reducing regenerative competence (Aim 1) and better understand the DLK/LZK-dependent gene regulatory network (Aim 2). I will then investigate whether gene therapy can restore regenerative competence to RGCs after DLK/LZK inhibition (Aim 3), with the goal of identifying treatments that can be both neuroprotective and pro-regenerative.

Project Details

These studies will distinguish new mechanisms responsible for cell death versus axon regeneration by investigating downstream transcriptional mechanisms of DLK and LZK. Therapies that inhibit DLK/LZK signaling show strong RGC neuroprotection in mouse models, but the lack of axon regenerative competence is a key obstacle to the utility of such treatments to restore vision in patients. I will focus on candidate transcription factors downstream of DLK and LZK and will allow me to manipulate transcriptional mechanisms to differentially regulate RGC death and axon regeneration. Clinical therapies for glaucoma are limited by our insufficient knowledge of how the disease triggers RGC death. Recent studies in animal models have identified enzymes (protein kinases) that directly link the axonal injury to apoptosis, and while blocking these signaling events is neuroprotective, these therapies eliminate the ability for cells to regrow and reconnect to the brain which is essential for visual repair. My work will investigate how RGCs regulates cell death versus axon regeneration through transcriptional networks and can identify novel targets.