人双孔钾离子通道TREK-1的果蝇同源物ORK1与神经认知关系的研究

Major depressive disorder (MDD) is a complex and neurological disorder, which affects about 10% of the world population and represents the second biggest financial and social burden due to its high ratio of recurrence, suicide and disability. The cognitive dysfunction of MDD is hard to be well controlled by antidepressant treatment, which has been thought as one of the main risk factor of chronic and relapse of the disease. However, the mechanism of the cognitive disorder in MDD is still unknown. Recently, the two-pore domain potassium channel TREK-1 has been identified to be closely related to the etiology of main depression and its cognitive impairment. The understanding of the role of TREK-1 function involved in MDD is needed.. ORK1 have been revealed as the Drosophila homologue of the two-pore domain potassium channel TREK-1 through Medline analysis. The present study will try to dissect the role of ORK1 in neural cognitive dysfunction based on a Drosophila experimental model. The possible biological mechanism will be investigated for the therapeutic effect of antidepressant drugs using neural biological approach, etc. Finally, we will further prove the functional homology of two genes by genetic rescue experiment, although the structure and number of two-pore domain is similar between the Drosophila ORK1 and mammalian TREK-1 proteins. In summary, the present project is expected to clarify the molecular mechanism of Drosophila ORK1 in neural cognition, and hopes to provide the new ideas and evidences for the exploration of the etiology and therapy of main depression and its cognitive impairment.

抑郁症是人类最为常见的精神障碍，因其高发病率，高复发率，高自杀率，高致残率造成沉重的经济和社会负担。抗抑郁治疗难以治愈抑郁症的认知障碍，后者是疾病慢性化和反复发作的危险因素。然而抑郁症认知障碍的发病机制至今不明，其最新研究表明人双孔钾离子通道TREK-1与抑郁症认知障碍关系密切，但确切分子机制不明。本课题在使用Medline分析证实人类双孔钾离子通道TREK-1在果蝇中同源物为ORK1的基础上，采用细胞培养和神经生物学等实验方法以果蝇为模式生物同时引入抗抑郁药物干预深入探讨ORK1与神经认知的关系。同时使用遗传挽救实验说明ORK1与人双孔钾离子通道TREK-1在功能上的保守性，进一步证明两基因的同源性；总之，本课题期望阐明人双孔钾离子通道TREK-1的果蝇同源物ORK1在神经认知障碍中的分子机制，从而为探讨抑郁症认知障碍分子机制提供新的思路和证据。

抑郁症是人类最为常见的精神障碍，因其高发病率，高复发率，高自杀率，高致残率造成沉重的经济和社会负担。抗抑郁治疗难以治愈抑郁症的认知障碍，后者是疾病慢性化和反复发作的危险因素。然而抑郁症认知障碍的发病机制至今不明，所以明确发病机制，对抑郁症认知障碍的治疗具有深远意义。最新研究表明人双孔钾离子通道TREK-1与抑郁症关系密切，但TREK-1是否与睡眠和认知相关还不明确。本课题尝试去检测ORK1（TREK1在果蝇中的同源物）在果蝇中睡眠和认知的作用。突变体和过表达的果蝇被确定。另外睡眠分析和短期记忆实验分别被用来检测突变体和过表达ORK1果蝇的睡眠和短期记忆，结果显示突变体果蝇较野生型果蝇的学习指数明显增加。然而ORK1突变体果蝇的睡眠时间明显减少。跟ORK1突变体果蝇相反，我们发现ORK1过表达果蝇能够增加睡眠时间和降低学习指数。我们的结果提示ORK1在调节果蝇睡眠和短期记忆中发挥重要的作用。