REMYLINATION AS A MECHANISM FOR SPINAL CORD REPAIR

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 脱髓鞘是人类和实验动物创伤性脊髓损伤（SCI）后功能障碍的重要原因。我们假设脱髓鞘的髓鞘再生，但在其他方面完整的轴突，将促进功能恢复。我们的初步数据显示，少突胶质细胞前体细胞（OPCs）移植和D15 A（一种具有NT 3和BDNF活性的新型神经营养因子）的联合应用部分恢复了挫伤性SCI后的电生理和行为功能。然而，许多移植的OPCs仍然未分化。初步数据还显示SCI后Notch信号的上调和Notch信号的激活抑制体外OPCs的少突胶质细胞分化。我们提出阻断抑制性Notch信号传导、增加少突胶质细胞分化生长因子D15 A的表达和递送已知增强髓鞘形成的生长因子的组合将进一步促进移植的OPCs的髓鞘再生并导致更大的功能恢复。我们将在一种新的临床相关的大鼠挫伤性SCI模型中测试这些策略，该模型的损伤严重程度可以调整，以引起足够的髓鞘和/或轴突损失，从而导致特定的行为和电生理缺陷，但也可以充分保留脱髓鞘轴突，使髓鞘再生。客观和敏感的电生理和行为测试将被用来检查是否增加髓鞘再生将增强功能恢复在这个挫伤性SCI模型。总的来说，这些实验将为确定脊髓损伤的髓鞘疗法提供基础。有三个具体目标。 目标1：为了测试阻断抑制性Notch信号传导和增加移植的OPCs中D15 A的表达的组合是否会导致急性SCI后增强的髓鞘再生和功能恢复。这将确定移植的OPCs在成年损伤脊髓中分化为少突胶质细胞的机制。 目标二：为了测试增强少突胶质细胞成熟和髓鞘形成的生长因子的表达的增加是否将进一步促进移植的D15 A + Notch-OPC的髓鞘再生并促进急性SCI后的功能恢复。这将提供重要的洞察机制控制的成熟和髓鞘再生的少突胶质细胞在受损的脊髓。 目标3：测试急性SCI中建立的最佳组合策略是否促进慢性损伤脊髓的髓鞘再生和功能恢复。这将确定策略，以促进功能性髓鞘再生在慢性损伤的脊髓。

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.