下丘脑SIK1-CRTC1通路在抑郁症病理过程中的作用及机制研究

下丘脑-垂体-肾上腺（HPA）轴功能亢奋在慢性应激诱发抑郁症的过程中十分重要，但其分子机理依旧不明。我们推测慢性应激通过减少下丘脑内盐诱导激酶1（SIK1）表达，引发其胞浆CREB转录调节共激活因子1（CRTC1）去磷酸化而入核增加并结合CREB，促进核内CREB活性并使得CRF转录合成增加，最终导致HPA轴亢奋，诱导抑郁症。本项目综合采用多种手段，研究慢性应激对下丘脑SIK1-CRTC1通路功能水平的具体影响；研究下丘脑SIK1-CRTC1通路的改变能否模拟慢性应激，诱发各种抑郁样症状，且该效应是否通过调控HPA轴亢奋所致；研究以下丘脑SIK1与CRTC1为分子干预靶点能否逆转/阻止慢性应激，产生抗抑郁效应；研究氟西汀、文拉法辛等临床抗抑郁药物是否作用于下丘脑SIK1-CRTC1系统，后者是否参与其抗抑郁机理。本研究将拓展对抑郁症发病机理的认识，发现新型抗抑郁靶点，具有显著临床应用价值。

Hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis is critical for chronic stress-induced depression, and however, the underlying molecular mechanisms remain elusive. We assume that chronic stress induces HPA axis hyperfunction and depression via the following pathway: 1, decreasing the expression of salt-inducible kinase 1 (SIK1) in hypothalamus; 2, leading to dephosphorylation of cytoplasmic CREB regulated transcription coactivator 1 (CRTC1) and its transportation into nucleus; 3, increased CRTC1-CREB binding in nucleus; 4, enhanced CREB activation and more biosynthesis of CRF. Here we are going to use various methods to explore: (1) The molecular effects of chronic stress on hypothalamic SIK1-CRTC1 pathway. (2) Whether dysfunction of hypothalamic SIK1-CRTC1 pathway modulates depression, leading to various depressive-like symptoms? Are these effects mediated by modulating the function of HPA axis ? (3) Whether targeting hypothalamic SIK1 and CRTC1 prevents chronic stress and leads to antidepressant effects ? (4) Do those antidepressants used in clinical (fluoxetine, venlafaxine, etc.) have effects on hypothalamic SIK1-CRTC1 system? Is this system involved in their antidepressant mechanisms ? Collectively, this project will make further progress in the research of depression, developing novel antidepressant targets, and has notable clinical values.