法尼醇受体（FXR）通过CREB信号参与抑郁症病理生理过程的作用及机制研究

Depression is a kind of common mood disorder. Traditional anti-depressants have various defects such as the long-cycle treatment and the low cure rate. Investigation of the pathophysiological mechanisms of depression is necessary for searching and developing new anti-depressants. Farnesoid X receptor (FXR) is a novel nuclear bile acid receptor in the nucleus. It has been shown to inhibit autophagy-associated gene expressions through interaction with cAMP response element binding protein (CREB). However, the role of FXR in depression remains unclear. Our recent work showed that FXR was correlated positively to depression in mice, and its expression level and interaction with CREB in hippocampus were markedly increased in mice suffering from depression. Given the critical role of the CREB-regulated hippocampal brain derived neurotrophic factor (BDNF) signal dysfunction in the development of depression, we will explore the role of FXR in depressive behaviors and pathophysiological changes, the relationship of FXR with the CREB-BDNF signal, as well as the molecular basis for the FXR-mediated regulation of depression through CREB signals. We will also investigate whether interruption of FXR-CREB interaction using small peptide affects the development of depression. The ultimate results will answer whether FXR can be a potential novel target for depression therapy, and provide a theoretical basis for the design and synthesis of the new anti-depressants targeting FXR.

抑郁症是一种常见的心境障碍疾病，传统抗抑郁药存在用药周期长、治愈率低等缺点，深入研究抑郁症发病机制、发现可供药物调控的新靶标意义十分重要。法尼醇受体（FXR）是核内一种胆汁酸受体，能通过与CREB结合，抑制由CREB介导的自噬基因表达，但其在抑郁症病程中的作用尚不明确。我们发现小鼠海马FXR与抑郁症具有正相关性，罹患抑郁症小鼠海马FXR表达水平及FXR-CREB相互作用显著增加。鉴于由CREB调控的海马BDNF信号功能失调是抑郁症发生的关键，本研究将借助基因干预等手段，阐明海马FXR在抑郁症行为学和病理生理学改变中的作用及其与CREB-BDNF信号的关系，并探讨FXR通过这一信号调控抑郁症发生的分子基础，随后应用小分子多肽研究打破FXR-CREB相互作用是否影响抑郁症发生。研究成果有望明确FXR是否能成为潜在的抑郁症药物治疗新靶标，并为设计与合成靶向FXR的抑郁症新型抑制剂奠定理论基础。

抑郁症是一种常见的心境障碍疾病，传统抗抑郁药存在用药周期长、治愈率低等缺点，深入研究抑郁症发病机制、发现可供药物调控的新靶标意义十分重要。法尼醇X受体（farnesoid X receptor, FXR）是核内一种胆汁酸受体，能通过与CREB结合抑制由CREB介导的自噬基因表达，其在抑郁症病程中的作用尚不明确，本研究主要解决FXR如何参与抑郁症病理生理学过程这一问题。我们发现小鼠大脑原代培养神经元和小鼠/人大脑组织均表达有FXR mRNA和蛋白。在原代培养神经元中，FXR在细胞核中大量分布，但在体内神经元中FXR主要定位于细胞质。不论是在离体培养还是在体神经元中，核内FXR均呈球形点状分布。在小鼠原代神经元和脑组织中，FXR配体GW4064和CDCA可增加小异源二聚体伴侣表达。CUS可上调海马CA1区FXR蛋白表达量，但不影响海马齿状回和内侧前额叶皮层FXR表达。在正常对照和CUS模型中，海马CA1区FXR过表达可引发或加剧小鼠在悬尾、强迫游泳、糖水消耗和旷场实验中的抑郁样行为，而FXR基因沉默则逆转小鼠抑郁样行为。FXR的这种作用与其改变CREB-BDNF信号有关：(1) FXR shRNA可逆转由CUS诱导的海马CA1区CREB磷酸化水平和BDNF蛋白表达量下降；(2) FXR过表达可进一步促进CUS诱导的海马CA1区BDNF蛋白表达量减少；(3) 抑制CREB BDNF信号可以阻断FXR shRNA对CUS所致小鼠抑郁样行为和海马CA1区BDNF蛋白表达量减少的逆转作用。打破FXR-CREB相互作用可逆转CUS引起的小鼠抑郁样行为、海马CA1区CREB磷酸化水平降低和BDNF蛋白表达量减少。应激环境下，FXR对CREB信号的抑制作用由海马CA1神经元CRTC2细胞浆转位介导。概括而言，我们的研究首次证实FXR在小鼠大脑神经元和小鼠/人大脑组织中的表达，这为今后深入探索FXR在中枢神经系统疾病中的作用奠定了扎实的基础。我们还发现由FXR上调和FXR-CREB相互作用增强引起的海马CA1神经元CRTC2细胞浆转位及CREB信号功能减弱是慢性应激诱发抑郁症的关键机制，该发现不仅增强了我们对FXR-CREB复合物在抑郁症形成中作用的认识，还进一步明确了海马CRTC2在抑郁症发病中的重要性。选择性打破CA1神经元FXR-CREB相互作用是研发抗抑郁药物的潜在策略。