肿瘤坏死因子α与食欲素参与帕金森病伴快速眼动期睡眠行为异常（RBD)发病的分子病理机制的研究

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia associated with loss of muscle atonia, vivid dreaming, and a wide spectrum of behaviors which can be violent in nature. RBD is one of the most frequent and prominent sleep disorders among Parkinson's disease (PD) patients. Hypocretin/Orexin regulates arousal and wakefulness. Published data demonstrate that Hypocretin knockout mice have frequent RBD. We have previously demonstrated that tumor necrosis factor alpha (TNF-a) impairs Hypocretin system by decreasing Hypocretin and receptor expression. TNF-a level is significantly increased, while Hypocretin is significantly decreased, in cerebrospinal fluid (CSF) of PD patients. We hypothesize that increased TNF-a level leads to decreased Hypocretin and TNF-a-induced decrease of Hypocretin contributes to RBD in PD patients. To test our hypothesis, the role of TNF-a in regulation of Hypocretin and RBD will be examined in vivo in animal models. In addition, we will study the association of CSF Hypocrein level with RBD in PD patients to further understand the molecular mechanism of RBD in PD patients. The long term goal is to identify the biomarkers for early diagnosis of PD and provide mechanism for early intervention of PD patients.

快速动眼睡眠（REM）期睡眠行为障碍（RBD）是以REM睡眠期生动的梦境和梦境相关的暴力行为为特点。RBD是帕金森病（PD）常见的最有特征性的睡眠障碍，食欲素（Hypocretin）具有兴奋大脑皮层调节睡眠-觉醒的作用。已发表的研究成果证明食欲素基因敲除鼠有显著的RBD发生。我们的前期研究证明肿瘤坏死因子（TNF-α）通过蛋白质降解机制下调食欲素的表达和损害食欲素系统的功能。PD患者脑脊液的TNF-α显著增高，食欲素显著下降。我们假设，TNF-α水平增高是导致帕金森患者食欲素水平下降和发生RBD的分子生物学机制。本研究拟通过动物模型确定食欲素系统与RBD发生的关系， 和确定TNF-α对食欲素系统的影响。本研究拟通过帕金森患者脑脊液食欲素水平与帕金森病之间的相关性，来进一步研究帕金森病患者发生RBD的分子机制。研究的最终目的是为PD患者寻找早期诊断的生物指标和早期干预的理论依据。

快速动眼睡眠（REM）期睡眠行为障碍（RBD）是以REM睡眠期生动的梦境和梦境相关 的暴力行为为特点。RBD是帕金森病（PD）常见的最有特征性的睡眠障碍，食欲素（Hypocretin）具有兴奋大脑皮层调节睡眠-觉醒的作用。已发表的研究成果证明食欲素基因敲除鼠有显著的RBD发生。我们的研究证明肿瘤坏死因子（TNF-α）通过蛋白质降解机制下调食欲素的表达和损害食欲素系统的功能。PD患者脑脊液的TNF-α显著增高，食欲素显著下降。我们的研究建议TNF-α水平增高是导致帕金森患者食欲素水平下降和发生RBD的分子生物学机制。本研究通过动物模型确定食欲素系统与RBD发生的关系和确定TNF-α对食欲素系统的影响。本研究通过帕金森患者脑脊液食欲素水平与帕金森病之间的相关性，来进一步研究帕金森病患者发生RBD的分子机制。研究的最终目的是为PD患者寻找早期诊断的生物指标和早期干预的理论依据。我们的动物研究和临床研究数据支持TNF-α参与调节食欲素表达、睡眠和认知，也揭示了神经炎症在包括阿尔茨海默病和帕金森病在内的神经退行性疾病中的作用。