抑郁症是一种常见的精神疾病，深入研究其发病机制、发现药物调控新靶标意义重大。CREB转录共激活子1（CRTC1）是CREB辅助调控因子，敲除CRTC1基因导致小鼠出现抑郁样行为。我们的结果显示慢性应激所致小鼠抑郁症与内侧前额皮层CRTC1蛋白减少密切相关，但有关CRTC1是如何减少的目前还不清楚。我们发现E3泛素连接酶Nedd4-1与抑郁症和内侧前额皮层CRTC1减少具正相关性，抑郁小鼠内侧前额皮层Nedd4-1表达和Nedd4-1-CRTC1相互作用显著增加。我们推测Nedd4-1可能通过与内侧前额皮层CRTC1结合促进CRTC1降解和抑郁症发生。本项目拟借助分子生物学等技术验证上述假说，并阐明抑制Nedd4-1-CRTC1相互作用是否影响抑郁症形成。研究成果有望明确Nedd4-1能否成为抑郁症药物治疗新靶标，并为研发基于抑制Nedd4-1-CRTC1复合物形成的抗抑郁策略奠定理论基础。

Depression is common psychiatric disease. Investigation of its novel mechanisms is necessary for searching new antidepressants. cAMP-response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) is an accessory regulatory factor for CREB. CRTC1 gene deficiency can induce depression-like behaviors in mice. Our preliminary results have shown that chronic stress-induced depression in mice is tightly associated with CRTC1 protein decrease in the medial prefrontal cortex. However, how this reduction happens remains unclear. We found that neural precursor cell expressed developmentally down-regulated 4-1 (Nedd4-1), an E3 ubiquitin ligase, is correlated positively with depression and CRTC1 protein decrease in the medial prefrontal cortex. Further, the expression of CRTC1 as well as Nedd4-1-CRTC1 interaction in the medial prefrontal cortex was increased markedly in mice suffering from depression. Thus, we speculate that Nedd4-1 may promote CRTC1 degradation and depression onset via directly binding to CRTC1 in the medial prefrontal cortex. In this project, we will use various techniques such as the molecular biology technique to examine this hypothesis and clarify whether inhibition of Nedd4-1-CRTC1 interaction would affect depression onset. Our results may help clarify whether Nedd4-1 could be a new target for depression therapy, and provide a theoretical basis for the development of antidepressive strategies which aim to inhibit Nedd4-1-CRTC1 complex formation.