室旁核QRFP-GPR103系统调控HPA轴亢奋在抑郁症发病机理中的作用研究

下丘脑-垂体-肾上腺（HPA）轴的功能亢奋在抑郁症病理机制中至为关键，然而其分子机理依旧不明。我们推测慢性应激引起下丘脑室旁核（PVN）内QRFP-GPR103系统的水平亢进，经由PKA/PKC/ERK/AKT通路促进核内CREB的Ser-133磷酸化激活，使得PVN内CRF转录合成增加，最终诱发HPA轴亢奋并导致抑郁症。本项目综合多种手段，研究慢性应激对PVN内QRFP-GPR103系统功能水平的具体影响；研究人为干预改变PVN内QRFP-GPR103系统能否模拟慢性应激，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PVN内QRFP与GPR103为药理靶点能否逆转阻止慢性应激，产生抗抑郁效应；研究临床抗抑郁药物（氟西汀、文拉法辛、曲唑酮及米氮平）能否作用于该系统，且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 in the pathophysiology of depression, and however, the underlying molecular mechanisms remain elusive. We assume that chronic stress induces depression via the following pathway: 1, enhancing the level of the QRFP-GPR103 system in paraventricular nucleus (PVN) of hypothalamus; 2, leading to Ser-133 phosphorylation of nuclear CREB via the PKA/PKC/ERK/AKT signaling pathway; 3, increased biosynthesis of CRF in PVN; 4, hyperfunction of HPA axis. Here we are going to use various methods to explore: (1) The molecular effects of chronic stress on the QRFP-GPR103 system in PVN. (2) Whether artificial dysfunction of the QRFP-GPR103 system in PVN modulates depression, leading to various depressive-like symptoms? Are these effects mediated via modulating HPA axis? (3) Whether targeting QRFP and GPR103 in PVN prevents against chronic stress and leads to antidepressant effects? (4) Do those antidepressants used in clinical (fluoxetine, venlafaxine, trazodone and mirtazapine) produce effects on this 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.