REMYLINATION AS A MECHANISM FOR SPINAL CORD REPAIR

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Demyelination contributes to the dysfunction after the traumatical spinal cord injury (SCI) in both humans and experimental animals. We hypothesize that remyelination of demyelinated, but otherwise intact axons, will facilitate the functional recovery. Our preliminary data showed that the combination of oligodendrocyte precursor cells (OPCs) transplantation and administration of D15A, a novel neurotrophin with both NT3 and BDNF activities77 partially restored electrophysiological and behavioral function after contusive SCI. However, many transplanted OPCs remained undifferentiated. Preliminary data also showed up-regulation of Notch signaling after SCI and activation of Notch signaling inhibited oligodendrocyte differentiation of OPCs in vitro. We propose that combination of blocking inhibitory Notch signaling, increasing the expression of oligodendrocyte differentiation growth factor D15A and delivery of growth factor(s) known to potentiate myelination will further promote remyelination from engrafted OPCs and leads to greater functional recovery. We will test these strategies in a novel, clinically relevant model of rat contusive SCI whose injury severity can be adjusted to cause enough loss of myelin and/or axons to result in specific behavioral and electrophysiological deficits but also sufficient sparing of demyelinated axons to enable remyelination. Objective and sensitive electrophysiological and behavioral tests will be used to examine if the increased remyelination will enhance functional recovery in this contusive SCI model. Collectively, these experiments will provide a foundation to identify myelin-based therapies for SCI. There are three specific aims. Aim 1: To test if the combination of blocking inhibitory Notch signaling and increasing the expression of D15A in transplanted OPCs will lead to enhanced remyelination and functional recovery after acute SCI. This will identify the mechanism through which engrafted OPCs differentiate into oligodendrocytes in the adult injured spinal cord. Aim 2: To test if increasing the expression of growth factors that potentiate oligodendrocyte maturation and myelination will further promote remyelination from the grafted D15A+Notch- OPCs and facilitate functional recovery after acute SCI. This will provide important insight into mechanisms controlling the maturation and remyelination by oligodendrocytes in the injured spinal cord. Aim 3: To test if the optimal combinatory strategies established in acute SCI promote remyelination and functional recovery in the chronically injured spinal cord. This will identify the strategy to promote functional remyelination in the chronically injured spinal cord.