Building a Molecular Atlas of Macrophage Contributions to Successful Spinal Cord Regeneration

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Spinal cord injury (SCI) induces a cascade of cellular events as severely damaged cells undergo apoptosis and assorted immune cells migrate to the injury. This immune response is critical to the long-term outcome, with inflammation playing an important role in secondary damage, wound repair and fibrotic scar formation. Despite recent advances, regenerative capacity in humans following SCI remains low. One valuable way to inspire new progress is to turn to other organisms which exhibit spontaneous recovery from SCI to explore the mechanisms that they use in regeneration. Among vertebrates able to regenerate, the frog Xenopus tropicalis is of particular interest because it shows developmentally-modulated regenerative capacity, able to regenerate its spinal cord in tadpole stages yet unable to regenerate in adult stages. As in other regenerative vertebrates, macrophages, including spinal cord resident microglia, are required for successful regeneration in young tadpoles, suggesting a conserved intimate association of the immune system with regeneration. In this proposal, I will spatially map the immune and neural cell states that follow SCI in efficient regeneration. From this multidimensional dataset, I will identify candidate beneficial immune factors and use genetic tools to test the necessity of these factors in successful spinal cord regeneration. Next, I will test the necessity of macrophages in juvenile spinal cord regeneration and comprehensively analyze changes in the macrophage response to SCI that coincide with a loss of regenerative capacity in frogs. Together, the generation of spatiotemporal atlases of successful regeneration, functional investigations into immune system modulation, and careful annotations of the incremental cell state alterations that accompany impaired regeneration, will provide a rich database from which to generate novel therapeutic candidates to promote neuronal survival and regeneration following SCI in humans. This fellowship will be completed under the mentorship of Dr. Cole Trapnell and Dr. Andrea Wills at the University of Washington, where I will have ample interactions with a vibrant community of researchers in the fields of neuroinflammation, regeneration, and transcriptomics. The primary training goals of this proposal are uniquely crafted to aid my career progression and will enhance my neuroimmunology background, expand my technical expertise, bolster my statistical training, improve my scientific communication skills, and increase my leadership experience. At the conclusion of this fellowship, I will have an established research program and will be well-positioned to advance into an independent position.