脊髓损伤后少突胶质细胞-小胶质细胞正反馈损伤回路介导脱髓鞘病变的机制研究

Spinal cord injury (SCI) is a devastating traumatic disease of central nervous system, which would lead to permanent neurological dysfunction post-injury. Despite of the increasing studies within the pathophysiological field of SCI, little is known by now. In our preliminary studies, we observed the over-expression of inflammatory cytokines after SCI, as well as the vacuolization of the myelin sheath and the inhibition of spinal evoked potentials. Hence, we hypothesize that the oligodendrocyte injury and demyelination induced by inflammatory cells, especially the microglia, plays a significant role after SCI, which could probably be interpreted by our theory of "oligodendrocyte-microglia positive feedback circuit". So this project aims to demonstrate the effects of this "positive feedback circuit" on the demyelination after SCI using the modified SCI model through in vivo and in vitro studies. Also, profound regional hypothermia will be performed as an experimental treatment to this circuit. If successful, these studies will provide increase access to the post-injury pathophysiology, extent the research contents and methods in SCI field and offer a potential therapeutic method and target against post-traumatic demyelination.

脊髓损伤（SCI）是一类严重的神经系统损伤性疾病，患者伤后可永残留神经功能障碍，给家庭和社会带来沉重负担，因此越来越受到人们重视。但目前对其病理生理机制仍缺乏全面深入的认识。我们在前期研究中发现SCI后各种炎症介质表达增多、髓鞘空泡化明显、脊髓诱发电位明显受抑制，由此我们推测炎症细胞（尤其是小胶质细胞）介导的少突胶质细胞损伤及脱髓鞘病变在SCI后的继发性损伤中起重要作用，而我们提出的"少突胶质细胞-小胶质细胞正反馈损伤回路"假说可能是造成脱髓鞘病变的重要机制之一。故本项目拟通过体内、体外实验，借助经我们改进的SCI模型，探讨该"损伤回路"在SCI后脱髓鞘病变中的作用；同时利用我们建立的脊髓局部深低温干预模型对该回路进行治疗干预。此研究将使我们进一步加深对SCI后病理生理学机制的认识，丰富SCI领域的研究内容和方法，并为SCI后抗脱髓鞘病变提供潜在的治疗靶点和干预手段。

脊髓损伤(SCI)的病理生理机制目前仍缺乏全面深入的认识。在本课题中我们提出假说并证实：“少突胶质细胞-小胶质细胞正反馈损伤回路”是造成脱髓鞘病变的重要机制之一。本研究包括三方面内容：.第一部分(体内实验)：在大鼠钳夹型损伤模型中，我们发现脊髓损伤后7d髓鞘空泡化程度、少突胶质细胞损伤程度、小胶质细胞活化程度、炎症指标、谷氨酰胺及铁离子浓度最高，但是后肢运动功能评分经21d恢复仍然较差。 .第二部分(体外实验)：在损伤原代培养的少突胶质细胞后的培养液成分加入原代小胶质细胞后可见其活化增多，炎症介质释放明显增加。将激活的小胶质细胞培养液成分加入到正常少突胶质细胞中可见明显损伤。损伤后少突胶质细胞的培养液成分内谷氨酰胺、铁离子浓度明显升高。.第三部分（局部深低温干预实验）：大鼠脊髓损伤后局部深低温使大鼠肢体功能明显好转，损伤部位的脊髓脱髓鞘程度明显减轻，同时减少小胶质细胞活化程度，进而减少脊髓损害；局部深低温起保护作用的机制可能与抑制CSPGs、Nogo-A、RhoA和ROCK-II通路相关。.本研究提出的“少突胶质细胞-小胶质细胞正反馈损伤回路”加深了对SCI后病理生理学机制的认识，丰富了SCI领域的研究内容和方法，局部深低温治疗为SCI后抗脱髓鞘病变提供了一个潜在的治疗手段。