多模式康复训练改善帕金森病运动平衡障碍的分子机制研究

Parkinson’s disease (PD) is a common neurodegenerative disease with bradykinesia, hypermyotonia, tremor and balance disturbance. Oral drugs cannot improve the balance of PD patients. Impaired balance is known to be an important risk factor for fratures caused by falls in patients with PD, and is one of the major sources of disability in advanced stages of idiopathic PD. Our previous clinical study showed that the multi-modal exercise training, designed based on core stability training, could improve movement and balance function in patients with PD, but the mechanism is not clear. Whole genome expression profile of PD patients' blood provide strong support for the involvement of protein ubiquitination system and immune response, which have been provided related to the pathology of PD, in improving movement and balance function. In this study, we will study the hub-genes related to movement and blance function by weighted gene co-expression network analysis. In addition, we will compare findings from whole genome expression profile of PD patients' blood with whole genome expression profile of striatum, substantia nigra, cerebellum, motor cortex of PD model mice. Our study will help to uncover the mechanism of improving movement and balance function by multi-modal exercise training. Moreover, it may facilitate the development of biomarkers for movement and balance impairments and obtain gene-expression features of the key brain regions before and after rehabilitation exercises, which could provide new strategies for drug development.

帕金森病（PD）是以运动迟缓、肌张力增高、震颤及平衡功能障碍为突出表现的神经退行性疾病。口服药物不能改善其平衡障碍，患者常因为跌倒后骨折而致残。我们前期临床研究发现，以核心力量训练为基础的多模式康复训练能显著改善PD患者的运动及平衡功能，但其作用机制尚不清楚；分析训练前后外周血基因表达谱显示，多模式康复训练前后患者泛素蛋白酶体系统、炎症反应等基因簇表达水平发生明显改变，而上述基因簇与PD的发生及发展均密切相关。本研究拟采用权重基因共表达网络分析法进一步筛选训练前后与运动平衡功能改善密切相关的关键基因，同时比较PD模型小鼠训练前后外周血基因表达谱与纹状体、黑质、小脑及运动皮质基因表达谱演变的相互关系，探索多模式康复训练纠正PD运动平衡障碍的作用机制，期待找出运动平衡障碍相关的分子标志物，阐明训练前后PD不同脑区的基因表达谱变化特征，并为基于康复训练的PD新药研发提供思路。

帕金森病（PD）是以运动迟缓、肌张力增高、震颤及平衡功能障碍为突出表现的神经退行性疾病。口服药物不能改善其平衡障碍，患者常因为跌倒后骨折而致残。我们前期临床研究发现，以核心力量训练为基础的多模式康复训练能显著改善PD患者的运动及平衡功能，但其作用机制尚不清楚。分析训练前后外周血基因表达谱显示，PD患者T细胞等免疫相关信号通路基因表达明显上调，而康复训练后T细胞信号通路及原发性免疫缺陷相关通路基因表达均显著下调，破骨细胞分化相关通路基因及自然杀伤细胞介导的细胞毒作用相关通路基因表达上调。同时，我们筛选到可预测康复训练后PD进程的血液分子标志物：ODC1、Fyn、TRAF、PIKE (AGAP2)。进一步，对MPTP诱导的慢性PD模型小鼠训练前后外周血基因表达谱与纹状体、黑质、小脑及运动皮质基因表达谱演变的相互关系，结果显示四个脑区在昼夜节律相关通路及细胞外基质相互作用上共同改变。同时我们发现黑质、纹状体是响应PD运动康复的最重要的部位，突触相关通路及转运相关通路在运动后显著上调。本研究阐明了训练前后PD外周血及不同脑区的基因表达谱变化特征，揭示了康复训练改善PD运动平衡障碍的中枢及外周机制，并为基于康复训练的PD新药研发提供思路。