高水平尿素在慢性肾病并发抑郁症病理过程中的作用机制研究

慢性肾病（CKD）具有比其他慢性疾病更易并发抑郁症的特点，但原因不明。本课题组根据CKD患者具有高血尿素水平的临床特征，并在发现脑组织内高水平尿素与小鼠抑郁样行为的发生相关的前期工作基础上，拟以高水平尿素（及其水解产物氰酸盐）对内侧前额叶神经元的病理生理作用和分子机制为切入点，综合应用分子生物学技术、免疫学技术、电生理技术等，采用腺嘌呤诱导CKD小鼠模型、尿素通道蛋白敲除小鼠模型和高氰酸盐小鼠模型，以及体外尿素和氰酸盐负荷神经元/急性脑片模型，从分子、细胞、组织、整体动物水平通过探讨脑组织高尿素及氰酸盐水平对mTORC1-S6K信号通路的调控、对神经元突触结构与功能的影响，并分析上述病理变化与各种小鼠模型抑郁样行为的内在联系，进一步验证具有持续活性的点突变S6K腺相关病毒的逆转效果，最终阐明高水平尿素及氰酸盐在CKD并发抑郁症过程中的病理机制，为治疗CKD患者并发抑郁症提供新的药物靶点。

Chronic kidney disease (CKD) has high co-morbidity of depressive disorder in contrast to other chronic physical diseases, but its mechanism remains vague. On the basis of the urea accumulation appearing in CKD, and we previous demonstrated clues on the relationship between cerebral high-level urea and depressive disorder in mouse model. In this study, the pathophysiological role and regulative mechanism of urea (and cyanate, its hydrolysate) on neurons at medial prefrontal cortex as a breakthrough point. We would like to practice techniques in combination with molecular biology, immunology, and electrophysiology etc., on mouse models, such as adenine-induced CKD model, urea transporters knockout mouse and high cyanate model. We will also test it in vitro, such as on cultured neurons and acute brain slices. Together, we will demonstrate the regulative mechanism of high-level urea/cyanate on mTORC1-S6K pathway, the morphologic and functional effects on synapse, analysis the relationship between the pathophysiologic changes and the depression-like behavior in mouse model, and verify the rescue effect of continuous active point mutations p70 S6K adeno-associated virus by evidence from molecule to individual. Hence, by unveiling mechanism under high-level urea/cyanate causes CKD co-morbid depressive disorder, and provide new drug-targets and strategies of treatment to improve life quality of CKD patients.