After spinal cord injury, a plethora of cellular responses impact functional recovery. Neurons may be preserved or undergo cell death, axon degeneration and/or regenerative attempt. Astrocytes may become hypertrophic, seal off the injury epicenter and influence axonal response in complex ways. Other cell types such as fibroblasts/pericytes, microglia, macrophages also play important roles. Understanding how different cell types respond to injury, how their responses are regulated and how they contribute to functional recovery is critical for developing therapeutic intervention to promote functional repair after spinal cord injury. In the past, our lab has mostly focused on the molecular control of neuronal responses to injury, and in particular axon regeneration and sprouting following CNS injury. Regeneration is axonal growth from injured neurons and sprouting is axonal growth from uninjured neurons. Both may contribute to functional recovery. DLK and LZK are mammalian homologues of invertebrate DLK that has been shown to play important roles in axon regeneration in C. elegans and Drosophila. The role of mammalian DLK and LZK in spinal cord repair in not known. In the process of studying DLK (MAP3K12) and LZK (MAP3K13) in axonal repair after spinal cord injury, we have identified a critical role for LZK in astrocytic scarring. This result corroborates with published literature on Stat3 and Pten to illustrate an emerging theme that signaling pathways regulating axonal repair may also regulate astrocyte response to injury. In this proposal, we will comprehensively investigate the neuron and astrocyte specific roles of LZK and DLK in the multicellular response to spinal cord injury using an array of inducible loss and gain of function mouse genetic lines. Downstream effectors of DLK and LZK will be identified through transcriptomic analyses in neurons and astrocytes. Functional synergies or redundancies will be tested between DLK and LZK, and the interaction with other signaling pathways including Stat3 and Pten will be tested as well. Together, these studies will determine the contribution of DLK and LZK in axonal repair and astrocyte response after spinal cord injury, which may pave the way for therapeutic development targeting these molecules to promote repair and recovery after spinal cord injury.

Public Health Relevance

The proposed study will investigate the role of LZK and DLK, a pair of MAP kinase kinase kinases, in the multicellular responses to spinal cord injury, which will provide novel insight on the neuron intrinsic and extrinsic regulation of axonal repair after spinal cord injury. If manipulating LZK and/or DLK is found to enhance tissue and axonal repair after spinal cord injury, this would pave the way to develop therapeutic intervention targeting LZK and/or DLK. The ultimate goal is to improve the quality of life for people with spinal cord injury or related neurological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS093055-06
Application #
9981399
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Bambrick, Linda Louise
Project Start
2015-05-01
Project End
2025-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
6
Fiscal Year
2020
Total Cost
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
Meves, Jessica M; Geoffroy, Cédric G; Kim, Noah D et al. (2018) Oligodendrocytic but not neuronal Nogo restricts corticospinal axon sprouting after CNS injury. Exp Neurol 309:32-43
Narang, Aarti; Zheng, Binhai (2018) To Scar or Not to Scar. Trends Mol Med 24:522-524
Chen, Meifan; Geoffroy, Cédric G; Meves, Jessica M et al. (2018) Leucine Zipper-Bearing Kinase Is a Critical Regulator of Astrocyte Reactivity in the Adult Mammalian CNS. Cell Rep 22:3587-3597
Geoffroy, Cédric G; Meves, Jessica M; Zheng, Binhai (2017) The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms. Neurosci Lett 652:41-49
Akassoglou, Katerina; Merlini, Mario; Rafalski, Victoria A et al. (2017) In Vivo Imaging of CNS Injury and Disease. J Neurosci 37:10808-10816
Chen, Meifan; Geoffroy, Cédric G; Wong, Hetty N et al. (2016) Leucine Zipper-bearing Kinase promotes axon growth in mammalian central nervous system neurons. Sci Rep 6:31482
Meves, Jessica M; Zheng, Binhai (2016) Synaptic Suppression of Axon Regeneration. Neuron 92:267-269
Ma, Hsiao-Yen; Xu, Jun; Liu, Xiao et al. (2016) The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in Alcoholic Liver Disease. Curr Pathobiol Rep 4:27-35
Geoffroy, Cédric G; Hilton, Brett J; Tetzlaff, Wolfram et al. (2016) Evidence for an Age-Dependent Decline in Axon Regeneration in the Adult Mammalian Central Nervous System. Cell Rep 15:238-46
Eckharter, Christoph; Junker, Nina; Winter, Lilli et al. (2015) Schwann Cell Expressed Nogo-B Modulates Axonal Branching of Adult Sensory Neurons Through the Nogo-B Receptor NgBR. Front Cell Neurosci 9:454

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