HPA轴亢进是抑郁症重要病理，但由于其机制不明，基于HPA轴的抗抑郁药物匮乏。我们前期研究发现海马nNOS通过调控GR介导HPA轴亢进。另外，海马端粒酶与抑郁症及神经元发生相关。同时发现，海马nNOS调控端粒酶，但其意义与机制不明。本项目运用nNOS基因敲除，TERT基因敲除、过表达、条件性基因敲除等模式小鼠，TERT过表达病毒、RNA干扰、工具药、细胞与切片培养、成年干细胞分选与培养、蛋白质芯片、微球包载病毒等技术方法着重研究：1. 海马nNOS-端粒酶-神经干细胞的增殖、分化及新生神经元的可塑性、环路构建在HPA轴亢进中的作用及机制；2. 开发用微球包装包载有TERT基因全长的逆转录病毒载体，经鼻腔给药探索抑郁症基因治疗策略。通过上述研究，将阐明海马nNOS-端粒酶在抑郁症HPA轴亢进中的作用和机制，并建立针对海马端粒酶特异性靶点的抑郁症基因治疗策略，为认识和治疗抑郁症开辟新的领域。

Hyperactivity of HPA axis is the hallmark of depression. Because the mechanism remains unknown, there is basically no using antidepressant developed base on HPA axis. Our previous study find that nNOS in the hippocampus mediates HPA axis hyperactivity via GR. Moreover, we find that telomerase in the neuronal stem cells in the hippocampus are involved in the pathology of depression and the modulation of neurogenesis. We also find that hippocampal nNOS regulates telomerase, but the mechanism and significance of which remains unclear. Here, we are going to use technologies including nNOS knockout, TERT knockout, overexpression, conditional knockout mice, TERT overexpression virus, TERT interference, tool drugs, cell and tissue culture, adult neuronal stem cell sorting and culture, protein chip, microsphere and so on to study two questions. 1. The function of “hippocampal nNOS-telomerase- proliferation and differentiation of neuronal stem cell and neuronal plasticity and circuitry integration of new born neurons pathway” in the pathology of HPA axis hyperactivity. 2. To develop a gene therapy strategy for depression by nasal administration of a PLG- microsphere vehicle carrying RV-TERT-GFP. In this study, we will reveal the role of hippocampal nNOS-telomerase pathway and its mechanism in the pathology of HPA axis hyperactivity and will provide a new therapy strategy for curing depression targeting telomerase in the neuronal stem cells in the hippocampus, providing new insights into the mechanisms and the treatment of depression.