经鼻-脑通路利用神经保护短肽Humanin干预抑郁动物模型：效力与机制研究

Major depressive disorder involves hippocampal neurons atrophy, cell apoptosis accelerates and neuronal regeneration disorder. Humanin, a short peptide found in the brains of patients with Alzheimer's disease, is characterized of its unique neuroprotective effects. Humanin also could exerts its neuroprotective effects in a variety of stress and disease models, suggesting that it may have a potential relationship with depression. However, there is few research on the role and mechanism of Humanin in the treatment of depression. Therefore, on the basis of our previous work, we will design and construct a fusion gene (NT4-Humanin-Ant cDNA) which could pass through the blood-brain barrier (BBB). Then, the fusion gene cDNA will be linked into adeno-associated virus (AAV) vector to obtain NT4-Humanin-Ant/AAV. NT4-Humanin-Ant/AAV will be used to infect the nasal mucasa of mouse, transfecting the fusion gene into the nasal mucosa cells to build a “small processing plant” which could persistently excrete NT4-Humanin-Ant peptides. We intend to apply it to normal mice to observe the specific pathway of NT4-Humanin-Ant/AAV through the "nasal -brain pathway". Next, we will nasal deliver NT4-Humanin-Ant/AAV to chronic unpredictable mild stress (CUMS) mice model to investigate its antidepressant effect. Furthermore, its functioning mechanism will be explored from the perspective of MDD hypothesis. We expect to establish a new approach and method for effective prevention and treatment of MDD.

抑郁症存在海马神经元萎缩、细胞凋亡加速、神经元再生障碍。Humanin是在阿尔茨海默病患者的脑内发现的具有独特神经保护作用的短肽，在多种应激和疾病模型中发挥神经保护作用，但其在抑郁症治疗中作用及机制尚无研究涉及。我们在既往工作基础上，利用基因嵌合技术设计并构建能通过血脑屏障的融合靶基因—NT4-Humanin-Ant cDNA，将融合肽cDNA 连入腺相关病毒（AAV）载体中，得到NT4-Humanin-Ant/AAV，通过感染小鼠鼻黏膜，将融合肽cDNA 转基因到鼻黏膜细胞内，形成一个体内的“小加工厂”，持续分泌表达NT4-Humanin-Ant。我们拟首先将其用于正常小鼠以观察NT4-Humanin-Ant/AAV通过“鼻脑通路”的具体路径；随后将其用于抑郁模型小鼠以考察其抗抑郁效应，并从MDD发病假说出发探索其作用机制，期望通过本研究能够建立一种新型的有效治疗MDD的途径和方法。

抑郁症存在海马神经元萎缩、细胞凋亡加速、神经元再生障碍。Humanin是在阿尔茨海默病患者的脑内发现的具有独特神经保护作用的短肽，在多种应激和疾病模型中发挥神经保护作用，但其在抑郁症治疗中作用及机制尚无研究涉及。我们在既往工作基础上，利用基因嵌合技术设计并构建能通过血脑屏障的融合靶基因—NT4-Humanin-Ant cDNA，将融合肽cDNA 连入腺相关病毒（AAV）载体中，得到NT4-Humanin-Ant/AAV，通过感染小鼠鼻黏膜，将融合肽cDNA 转基因到鼻黏膜细胞内，形成一个体内的“小加工厂”，持续分泌表达NT4-Humanin-Ant。本项目中我们首先构建NT4-Humanin-Ant/AAV，建立不可预期慢性温和应激（unpredictable chronic mild stress, UCMS）抑郁模型，通过滴鼻将表达Humanin的病毒干预模型动物，发现Humanin干预后UCMS小鼠明显增加了对糖水偏好，强迫游泳中的不动时间减少，这表明通过鼻脑通路给药的Humanin具有抗抑郁效应。