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

项目摘要/摘要

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. The goal of the parent R01 was to identify the neuronal (Aim 1) and astrocytic (Aim 2) roles of DLK and LZK in axon and tissue repair after spinal cord injury. We have made substantial progress on both fronts. This diversity supplement aims to support a graduate student from an underrepresented background (an African American woman), who is asking the important questions on both the direct and indirect roles of astrocytic LZK in tissue preservation and axonal repair after injury. Specifically, the trainee will use a contusion injury model to assess the direct role of astrocytic LZK in tissue preservation and injury site resolution along with functional recovery using genetic gain and loss of function analyses. She will then profile the transcriptomic changes in the astrocytes using the RiboTag approach to discover potential mediators of LZK signaling in astrocytes. Using methods to stimulate corticospinal axon regeneration, the trainee will assess the effect of manipulating LZK-mediate astrocyte response on axonal repair. She will also map the epistatic relationship between LZK and STAT3 in regulating the astrocyte response to injury. This body of work along with the experimental techniques mastered in this process will propel the trainee to pursue a career in independent neuroscience research that has both scientific and translational value in future. These experiments complement the existing components in the parent R01 while remaining within the overall goal of the original application.