Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.

 描述(申请人提供)：医学上的大多数治疗进展集中在可接近的组织疾病，如凝固性疾病和肿瘤学，在这些疾病组织可以直接检查和操纵。要在分子水平上系统和全面地研究神经精神障碍，直接接触患者的神经元和神经胶质细胞是必不可少的。在这里，我们建议使用一种创新的方法，利用一种新的三维(3D)人类多能干细胞(HiPSC)神经分化方法，分别生成包括皮质兴奋性神经元(大脑皮层下类神经元)或腹侧端脑中间神经元(大脑皮层下类神经元)的神经球体。利用区域特异性遗传增强剂，我们计划对大脑皮层样球和大脑皮层下样球体进行荧光标记，并将它们融合在一起，以设计悬浮中的混合神经结构。通过对来自遗传型精神分裂症和自闭症谱系障碍(ASD)患者的HiPSC进行的两区人前脑球体的一系列分析，我们旨在确定这些疾病背后的关键病理生理过程。

 DESCRIPTION (provided by applicant): Most therapeutic advances in medicine are concentrated in accessible tissue disorders, such as coagulopathies and oncology, where diseased tissue can be directly examined and manipulated. To systematically and comprehensively study neuropsychiatric disorders at the molecular level, direct access to neurons and glia from patients is indispensable. Here, we propose to use an innovative approach that leverages a novel tridimensional (3D) neural differentiation method of human pluripotent stem cells (hiPSC), to separately generate neural spheroids that include either excitatory neurons of the cortex (subpallium-like) or ventral telencephalic interneurons (subpallium-like). Using regional-specific genetic enhancers, we plan to fluorescently label pallium-like and subpallium-like forebrain spheroids and fuse them to engineer mixed neural structures in suspension. Using a series of assays in two-region human forebrain spheroids engineered from hiPSC derived from patients with genetic forms of schizophrenia and autism spectrum disorders (ASD), we aim to identify the key pathophysiological processes underlying these disorders.