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

通过在体外对人脑进行逐个改造，深入了解精神疾病。

• 批准号: 8957296
• 负责人: Sergiu Pasca
• 金额: $ 48.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8957296
• 关键词: 22q11.2; Address; Adult; Astrocytes; Autistic Disorder; Biological Assay; Biological Neural Networks; Blood Coagulation Disorders; Brain; Caliber; Complex; Development; Disease; Dorsal; Engineering; Enhancers; Functional disorder; Generations; Genetic; Goals; Human; Human Engineering; In Vitro; Interneurons; Label; Medial; Medicine; Mental disorders; Methods; Molecular; Mutation; Neurodevelopmental Disorder; Neuroglia; Neurons; Patients; Pattern; Phenotype; Pluripotent Stem Cells; Positioning Attribute; Process; Property; Prosencephalon; Schizophrenia; Series; Staging; Structure; Suspension substance; Suspensions; Syndrome; System; Therapeutic; Tissues; autism spectrum disorder; cell motility; excitatory neuron; fetal; innovation; insight; migration; neural patterning; neurodevelopment; neuropsychiatry; novel; oncology; prenatal; protocadherin 19; public health relevance; relating to nervous system

 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.

 描述（由申请人提供）：医学上的大多数治疗进展集中在可触及的组织疾病，如凝血病和肿瘤学，其中可以直接检查和操作患病组织。为了在分子水平上系统和全面地研究神经精神疾病，直接接触患者的神经元和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）的人多能干细胞（hiPSC）的神经分化方法，分别产生神经球体，包括兴奋性神经元的皮质（subpallium样）或腹侧端脑中间神经元（subpallium样）。使用区域特异性遗传增强子，我们计划荧光标记苍白球样和苍白球下样前脑球状体，并将它们融合到悬浮的混合神经结构中。使用一系列的测定在两个区域的人类前脑球状体工程从hiPSC来自遗传形式的精神分裂症和自闭症谱系障碍（ASD）的患者，我们的目标是确定这些疾病的关键病理生理过程。