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.
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.
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