The limited ability of axons in the adult mammalian central nervous system, consisting of the brain and spinal cord, to regenerate is a major obstacle to functional recovery from spinal cord injuries for which there is currently no effective treatment. Understanding the molecular components regulating neuron-intrinsic capacity to regenerate axons will facilitate the identification of potential therapeutic targets for axon repai. Leucine zipper-bearing kinase LZK/MAP3K13 is an appealing candidate regulator of mammalian axon regeneration because it is one of two mammalian homologues of the invertebrate dual leucine zipper-bearing kinase DLK-1/Wallenda required for the regenerative response in Caenorhabditis elegans and Drosophila melanogaster. The proposed project tests the hypothesis that LZK is a neuron- intrinsic positive regulator of mammalian axon regeneration. In the first aim, the effect of overexpressing or depleting LZK on neurite extension and regeneration will be established in vitro using various neuronal cell lines and primary neurons. In the second aim, axotomy- dependent regulation of LZK will be examined in vitro and in vivo by biochemical and immunohistochemical approaches, followed by identification of the downstream signaling effectors mediating the effect of LZK on axon regeneration. In the third aim, the requirement for LZK in axon regeneration will be examined in tamoxifen-inducible and sensory neuron-specific LZK null mice. The ability of LZK overexpression to promote axon regeneration will also be investigated in wildtype mice. Establishment of LZK as a regulator of axon regeneration in adult mammals and elucidation of its signaling components will provide the molecular basis for potential development of therapeutic interventions for spinal cord injuries and certain neurodegenerative diseases involving axonal damage.

Public Health Relevance

The main reason for the debilitating deficits, ranging from permanent loss of involuntary functions to paralysis, in individuals suffering from spinal cord injuries is the limited ability of the injured axons in the adult central nervous system to regenerate. Development of effective treatment for spinal cord injuries therefore requires a better understanding of the molecular events controlling axon growth. This project aims to identify neuronal regulators of mammalian axon regeneration and therefore bears the potential to uncover therapeutic targets for spinal cord injuries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS083186-02
Application #
8655461
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20))
Program Officer
Jakeman, Lyn B
Project Start
2013-05-01
Project End
2015-08-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$53,282
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chen, Meifan; Zheng, Binhai (2014) Axon plasticity in the mammalian central nervous system after injury. Trends Neurosci 37:583-93