唐氏综合症星形胶质细胞诱发脑发育异常与学习记忆功能下降的分子机制研究

唐氏综合症（DS）是最常见的先天性智力发育障碍性疾病。DS患者神经元变性的机制目前仍不清楚。究其原因，DS发病机制的研究主要依赖于小鼠模型，但小鼠难以模拟人的21号染色体三倍化。利用DS患者诱导性多潜能干细胞（iPSC）建立人源性嵌合小鼠可弥补这一缺陷。本课题组基于此开展了大量前期工作，发现DS-iPSC来源的星形胶质细胞（DS-Astro）具有神经毒性作用，可能是诱发神经元死亡和突触生成减少的“元凶”（Nat Commun，2014）。我们已建立了可呈现人DS早期表型的3D类脑和人源性嵌合小鼠模型，发现DS-Astro可引起学习记忆能力下降。本项目拟优化上述新型模型，从S100B，IFNAR1/IFNAR2及其下游的Jak-STAT信号通路，解析DS-Astro诱发毒性表型的分子机制，并探讨能否采用CRISPR/Cas9 技术或小分子化合物来改善人源性嵌合小鼠的脑发育异常和学习记忆能力。

Down syndrome is the most common intellectual disability and developmental delay. Previous studies have been focused on the pathological changes of neurons with the underlying mechanisms unclear. The reason is that mice model is the main tool to explore the pathogenesis of DS, but a bottle-neck problem in the field is that it is very hard for mice models to mimic the progress of human pathology caused by the triploid of 21 chromosome. The establishment of humanized chimeric mice using induced pluripotent stem cells (iPSC) from DS patients can solve this difficulty. Based on iPS technology, our previous study has demonstrated that astrocytes derived from the iPS cells of Down syndrome patients not only lost the neuronal supportive function, but also exhibited neurotoxic phenotype （Nat Commun，2014）. We further established the 3D cerebral organoid of Down syndrome and humanized chimeric mice models which shows early phenotype of Down syndrome, and found that astrocytes of Down syndrome, by themselves, could impair the learning and memory of chimeric mice. Therefore, it is possible that the glial abnormality may be a long overlooked pathological change of Down syndrome. In this project, we will investigate the function and mechanism of this toxic phenotype of astrocytes in Down syndrome from the points of inflammatory associated genes S100B, IFNAR1/IFNAR2 and their downstream Jak-STAT signaling. Then, we will correct the dosages of the key genes, screen protective small molecules, hoping to rescue the abnormal brain development of Down syndrome and improve the learning ability by correcting the phenotype of “toxic” astrocytes.