# Traumatic axonal injury in the visual system: role of dual leucine zipper kinase

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $509,574

## Abstract

PROJECT SUMMARY
Traumatic brain injury (TBI) is a very common problem with over 2 million new cases requiring medical
attention annually in the US. A neuropathology that is widely shared among various types of TBI and across
spectrum of severity is diffuse or traumatic axonal injury (TAI), a form of ultra-rapid deformation and disruption
of axons caused by rotational acceleration and shearing of brain tissue. In this project we use a visual model of
TAI and explore the hypothesis that the DLK-JNK signaling cascade, known to be activated in simple axotomy
lesions like nerve crush, triggers downstream degenerative effects of TAI in neurons projecting in the optic
nerve, i.e. retinal ganglion cells (RGCs). We ask three questions, in logical order: is DLK-JNK pathway
activated in visual TAI? If so, does DLK-JNK activation trigger retrograde degenerative effects in RGCs as in
simple axotomy models? And does blocking of the DLK-JNK pathway prevent or treat RGC degeneration and
related system impairments such as disconnection with CNS targets and loss of vision? To inflict TBI, we use
the impact acceleration model of diffuse TAI with which we have consistently produced primary optic nerve
injury in our laboratories. Our experimental subjects are conditional knockout mice for key members of the dual
leucine zipper kinase (DLK-JNK) cascade. We also employ CRISPR strategies to disrupt the initiating kinases
of the DLK-JNK cascade, DLK and LZK, and also treat wild-type injured mice with the DLK inhibitor sunitinib.
Our experimental readouts include kinase activation, cell death, axonal and terminal degeneration using
conventional and high-resolution (CLARITY) neuroanatomical methods, and behavioral measures of visual
acuity. Besides exploring the role of key members of the DLK-JNK signaling pathway in perikaryal and axonal
degeneration in visual TAI, the proposed experiments provide proof of concept for the protective or therapeutic
effect of DLK/LZK blockade in TAI. The project leverages the complementary strengths of our laboratories and
the design and experimental methods are supported by extensive preliminary studies. In Specific Aim 1 that
serves as the foundation of the proposal, we will determine whether TAI in the visual system is associated with
activation of the DLK-JNK signaling cascade in RGCs and we will identify key signaling molecules. In Specific
Aim 2, we will explore whether blocking JNK and DLK/LZK signaling with knockout/genome editing strategies
or pharmacological inhibition prevents or aborts RGC perikaryal and axonal degeneration in visual TAI. In
Specific Aim 3, we will determine whether blocking DLK/LZK activation with knockout/genome editing
strategies or pharmacological approaches prevents or aborts neural system impairments (visual disconnection
and dysfunction). Taken together, these experiments examine the role of the DLK-JNK pathway in neuronal
degeneration, disconnection, and dysfunction following TAI in a model CNS system an...

## Key facts

- **NIH application ID:** 9895809
- **Project number:** 5R01EY028039-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** VASSILIS E KOLIATSOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,574
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895809

## Citation

> US National Institutes of Health, RePORTER application 9895809, Traumatic axonal injury in the visual system: role of dual leucine zipper kinase (5R01EY028039-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9895809. Licensed CC0.

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