The Role of a Pair of MAP3Ks in the Multicellular Response to Spinal Cord Injury

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PROJECT SUMMARY / ABSTRACT 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. 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 was not known. Supported by this parent R01, our lab found a role for LZK in astrocyte response, and have now identified neuronal roles for DLK and LZK in axonal repair. This supplement aims to support a graduate student from an underrepresented background, who is asking the important questions on the context-dependent roles of DLK and LZK in neuronal response to injury. Specifically, the trainee will use an injury model where significant cell death occurs to interrogate whether the same sinaling pathway can influence both axon regeneration and cell death under different injury paradigms on the same neuronal type. Transcriptional profiling on DLK/LZK manipulated neurons will then identify potential downstream effectors of the signaling pathway. Together, these experiments offer great training potential for the student, and complements the existing experiments proposed in the parent R01 while remaining within the overall goal of the original application. Insights from the proposed study will pave the way for therapeutic development targeting these molecules to promote repair and recovery after spinal cord injury.