Carla Winter, Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, USA

Develop tract-specific regeneration strategies

Funded in: 2022, 2023, 2024

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Problem: Damaged axonal tracts lead to motor, sensory, and autonomic dysfunction
Target: Gain knowledge of underlying mechanisms for heterogeneous injury response
Goal: Combinatorial therapy targeting at multiple spinal projecting neurons` pathways

Spinal cord injury (SCI) is a devastating condition that leads to lifelong autonomic, sensory, and motor impairments, resulting in a dramatic decrease in quality of life. Unlike superficial wounds, the consequences of SCI are almost always permanent due to the overall inability of the central nervous system to regenerate and effectively re-wire spared tissue. This limited capacity for recovery has led to a race to identify factors promoting axon regeneration and neuroplasticity. Sadly, little clinically meaningful progress has been made to date.

This failure to develop a successful therapy is likely owed, at least partially, to the highly heterogeneous and cell-type specific nature of both SCI and treatment, which precludes the discovery of a singular, “silver-bullet” therapeutic. A particularly striking example of neurons with varied injury responses are spinal projecting neurons (SPNs) that connect numerous brain regions to the spinal cord. This population of neurons is functionally important, carrying different motor, autonomic, and sensory command signals from the brain to the spinal cord. These SPNs also exhibit varied injury responses, with certain populations exhibiting more resilience to injury and differing responses to treatment. This heterogeneity in injury response indicates that studies considering spinal tracts as singular, homogeneous units are lacking important single-cell resolution, thus resulting in treatments with limited regenerative and behavioural outcomes. The insufficient knowledge of these mechanisms underlying this heterogeneous injury response is a significant gap and may be the “missing link” in developing tailored and effective treatments for SCI.

Here, the researcher aims to develop a therapeutic for SCI by understanding what factors drive heterogeneous injury response in the functionally important SPNs. To achieve this goal, the neuroscientist will use single cell transcriptomics to characterize intact and injured adult mouse SPNs. Subsequently, she will use candidates identified via these transcriptomic analyses to develop a combinatorial therapeutic targeted at multiple SPN pathways.