Michael Sofroniew, University of California Los Angeles, Department of Neurobiology, Los Angeles, United States

Stimulation and support of propriospinal axon regeneration across chronic anatomically complete SCI

Funded in: 2018, 2019, 2020


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Problem: Complete, or large and serve, lesions do not leave significant spared connections

Target:  A mechanism-based, biological repair strategy that is successful at short times after SCI

Goal: Adaption of this strategy to chronic times after anatomically complete SCI

 

Many spinal cord injuries (SCI) are incomplete and leave some spared nerve fiber connections across the level of the injury. For such injuries there is steady progress in identifying rehabilitative, pharmacological and electrophysiological strategies to augment spared neural circuitry and improve functional outcome. Nevertheless, about 30% of SCI are regarded as anatomically complete, or large and serve, and have lesions that do not leave significant spared connections. For such injuries, rehabilitation or augmentation of spared circuits will be of limited benefit on their own. For these patients, restoring function will likely require biological repair, or neuroprosthetic technologies, or combinations of both. At present, there is an incomplete understanding of why nerve fibers fail to regrow across severe SCI lesions.

Our overall goals are to understand the causes for this failure and to develop a biological repair strategy that reliably restores functional neural connectivity across chronic, anatomically complete SCI. Our focus is on identifying biological mechanisms that are required to stimulate, support and attract the regrowth of injured nerve fibers across lesions. Building on work from multiple laboratories, we recently identified a mechanism-based, biological repair strategy for achieving robust regrowth of spinal cord nerve fibers across complete lesions in both mice and rats at short times after SCI. This strategy uses a combinatorial approach involving the injection of activators of genetic growth programs, followed by sequential injections of biomaterial depots that release chemoattractive factors. Our goals in the current project are to adapt this strategy to chronic times after anatomically complete SCI. Our work will provide rigorous, mechanistic evidence regarding the requirements to achieve the regrowth of spinal cord nerve fibers across severe complete lesions at chronic times after SCI. This work will advance the development of mechanism-based, reliable and clinically translatable repair strategies for restoring neural connectivity across severe, chronic SCI lesions.