非人类灵长类动物（猕猴）脊髓撞击损伤模型的建立和行为学评估

Spinal cord injury (SCI) is one of the catastrophic diseases that significantly affect the quality of life of the patients, and huge economic burden to their family and the entire society. Progresses on SCI research have been made in recent years,however, there is no effective treatment available in the clinic yet. One reason for the lack of effective treatment may be due to the fact that commonly used rodent models are less translational to the clinic. There are significant differences in anatomical structures and pathophysiolocial properties between rodents and human patients. Using non-human primates in the SCI research should bridge the rodent studies to humans, which is highly clinic relevant. However, to date, limited SCI studies have been done in nonhuman primates. In this application, we propose to develop a well-controlled, highly-reproducible spinal cord impact model in rhesus monkeys to establish a baseline for investigating injury mechanisms, and assessing recovery of function after SCI. The model is characterized by a firm veterbral stabilizaiton and accurate graded tissue displacements. When established, this model can be used to assess novel therapeutic interventions for patients with SCIs. Our SCI model on nonhuman primates will generate reproduce cord lesion to simulate the clinical situation of SCI. To evalate functional recovery following SCI, we will establish a series of sensitive behavioral assessments to detect motor and sensory deficit, which include the monkey corridor test (locomotors function) and Hargreaves test (sensory threshold). Compare with the rodent or other distantly related species, the nonhuman primate model will provide new insights into the pathophysiology of the disease and serve as preclinical platform for the new SCI therapies.

脊髓损伤（SCI）是机体遭遇的最具破坏性的外伤之一，其致残的后果给患者、家庭和社会带来严重负担。虽然实验室研究取得了一些成果，但向临床转化过程中遇到了困难。原因之一是实验室研究对象大多是啮齿类动物，其解剖结构、生理功能等与人类有很大的差异。而灵长类动物与人类十分接近，可以作为实验室成果向临床转化的中间平台。本研究将以猕猴作为研究对象，首次使用针对灵长类动物的专用重物坠落损伤仪，建立猕猴脊髓撞击伤模型，更好地模拟临床SCI情况。另外，灵长类动物脊髓损伤前后行为学及功能鉴定，在国际上并没有的统一标准，为准确评价非人灵长类SCI模型的稳定性、各种治疗措施的有效性等重要指标增加了难度。因此，本项研究我们将建立一系列有针对性、敏感的灵长类动物脊髓损伤行为学评估，并首次使用Hargreaves方法检测猕猴痛温觉反射。本课题将为国际上灵长类动物脊髓损伤行为学评价体系的完善和统一提供宝贵的资料。

脊髓损伤(spinal cord injury, SCI)是最具破坏性的外伤之一，往往导致损伤节段以下肢体严重的功能障碍，且修复程度极低，给患者、家庭和社会造成巨大的影响和经济负担。SCI的预防、治疗和康复已成为当今医学界的一大课题。然而从啮齿类动物研究中获得的有效结果难以在临床上直接应用，这是因为啮齿类动物和人类脊髓之间存在着明显的解剖学、功能、分子和病理学差异。如果这些结果用非人灵长类动物验证，将有助于在临床发展有前途的新的治疗策略。.本项研究，我们使用针对大型动物(猴)改良的LISA-L脊髓撞击器和棘突固定器，对猴实施两种严重程度的损伤-轻度(1.0mm)和中度(1.5mm)损伤，在成年猴身上成功建立脊髓撞击损伤模型。.我们根据猴在猴走廊和生活笼内的活动，创建了一个12分的MHS行为学评分系统，适合于髋、膝、踝关节运动评估，充分反映SCI后猴从截瘫到恢复的步态变化及下肢运动功能和脚趾功能改变。另外，SCI后下肢持物能力明显下降(p<0.001)；感知纤毛的触痛能力下降；对压痛的忍耐力下降，尤其是损伤急性期(p<0.05)；对热痛刺激的忍耐力下降(p<0.05)。.电生理评估发现，猴SCI后MEP反应率被明显抑制甚至消失(p<0.01)；SSEP反应延迟、振幅减小(p<0.05)。核磁共振成像(MRI)显示损伤后4h纵向纤维束在病变部位被中断而杂乱无章；7天、3、6个月高T2信号增加。.猴SCI节段连续切片、组织学鉴定发现：损伤中心的脊髓变窄(p<0.001)，组织缺损程度与撞击度正相关；HE染色及3D重建显示损伤中心组织结构紊乱，灰质及导水管连续性被空洞打断；损伤部位及腹侧外周的SMI31阳性轴突数量都显著减少(p<0.001)；LFB阳性的髓鞘丢失、数量明显减少(p<0.001)；损伤中心边缘未见有与大鼠SCI相似的GFAP阳性星型胶质细胞增生过度所致胶质瘢痕。.对50名志愿者和12名SCI患者的Hargreave’s测试，显示病患对红外刺激的热縮足反应时间显著延长(p<0.001)。.因此，我们使用LISA-L创建了一个新型可控、损伤精确的猴脊髓撞击损伤模型；创建一个新的猴MHS系统评估SCI后下肢运动功能；综合运用电生理、MRI、病理组织学等检测到损伤程度依赖的组织学变化，而这些变化与人类的病理变化相类似，进一步证明猴在SCI临床成果转化中的重要性。

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