应用囊泡转运原理筛选新生神经环路建立的微环境因子

Neural stem cell therapy appears to be promising for the treatment of neurodegenerative disorders. However, one of the bottle necks is the difficulty for new-born neurons to survive and synaptically integrate into the mature neural networks. It is essential to establish a highly efficient approach to study the key molecules in the micro-environment that controls the survival and synaptic integration of new-born neurons. We recently idientified two vesicle-trafficking pathways that depends upon Synaptotagmin (Syt) 1 and 10, two key members in Synaptotagmin family.In the preliminary experiments, we observed that pathways mediated by Syt1 and Syt10 control the survival and synaptic integration of new-born neurons in adult mouse olfactory bulb.These results suggest that the secretion of the key factors for neuronal survival and synaptic integration are mediated by Syt1 and Syt10. Based upon these observations, we will identify the unknown factors in the micro-environment that control the survival and synaptic integration of new-born neurons, by combining secretomics and Syt1/Syt10 loss-of-function. Furthermore, we will systematically examine the beneficial effects of the identified factors upon the new circuits formation in rodent model of neurodengenerative disorders.These results will potentially provide a highly efficient approach to study the micro-environmental factors for new-born neuronal survival and synaptic integration in adult brain.

干细胞治疗神经退行性疾病的关键在于新生神经环路的建立。这个过程依赖于脑内微环境中促进神经元存活和突触整合的关键因子。然而目前缺乏一种高效鉴别脑内微环境因子的手段。我们在神经元中发现两条重要的囊泡转运通路，分别依赖Synaptotagmin家族重要成员Syt1和Syt10（Cao et al., Cell 2011;The Journal of Neuroscience 2013）；并观察到Syt1和Syt10可控制成年小鼠脑内新生神经元的存活和突触整合（见研究基础）。在此基础上，本项目以嗅球中的新生神经元为研究对象，利用细胞囊泡转运原理建立一套高效研究方法，筛选新生神经元存活和突触整合的关键微环境因子，并在阿尔兹海默症小鼠模型上检验它们对新生神经环路建立的调控机制。本项目有望鉴定出一批过去未知的重要微环境因子，为探索"神经干细胞治疗神经退行性疾病"的道路提供重要理论支持。

成年动物脑内的新生神经元需要经过突触整合，才能行使正常的生理功能。本项目研究了成年小鼠嗅球内负责新生神经元突触整合的关键微环境因子。经过四年努力，我们较为合理地执行了本研究项目，已完成的科研任务包括：（1）研究 Synaptotagmin 家族成员和生长因子 IGF1 在嗅觉学习过程中调控成熟神经元突触传递效率的生理功能。已发表研究论文一篇（Neuron, 2017 年，项目组成员为第一作者和通讯作者）。（2）进一步研究这些重要蛋白分子在嗅球新生神经元存活和突触整合过程中的关键功能。相关研究结果正在撰写研究论文。（3）进一步分析了 Synaptotagmin 家族成员是否调控其他生长因子的释放，并初步探索这些生长因子在嗅球新生神经元存活和突触整合过程中可能扮演的重要角色，这一部分研究内容还在继续开展。这三部分研究初步揭示了成年小鼠嗅球中新生神经元突触整合的一些关键分子机制。