Investigation of the molecular mechanisms of intellectual disability using human-brain organoids

智力残疾（ID）是一种以认知能力和适应行为显著限制为特征的疾病，在成年前发病。全世界有1-2%的儿童患有躁郁症，造成了沉重的社会负担。由于高通量测序技术的最新进展，遗传学研究发现了2500多个与ID相关的基因，常染色体隐性ID占ID遗传原因的50%以上。相当一部分ID病例显示大脑解剖异常，如小头畸形和无脑畸形，提示该疾病的神经发育起源。然而，对ID的分子机制知之甚少，这限制了可能的干预和治疗方法。该项目的目标是利用人脑类器官研究ID的分子机制。我们已经确定了一组ID相关基因，这些基因编码参与RNA加工和修饰的蛋白质，这些基因发生突变的ID患者患有小头症。在这个项目中，这些基因在皮质发育中的功能将被研究，具体目标如下。目的1。目的：探讨id相关基因在人前脑类器官神经干细胞行为和神经元迁移成熟中的作用。利用单细胞RNA测序技术确定基因损伤后转录组的变化，并鉴定靶RNA。本课程旨在了解大脑发育的基本概念，包括人类皮层发育和神经发育障碍过程中的神经干细胞行为和神经元成熟。从技术上讲，学生将学习如何培养人类干细胞和脑类器官，并使用免疫组织化学、成像和计算分析来评估神经发育。此外，学生将有机会学习分子生物学对ID基因的遗传操作和生化方法来理解RNA过程

Intellectual disability (ID) is a condition characterized by significant limitation in cognitive ability and adaptive behaviours with disease onset before adulthood. ID affects 1-2% of children worldwide resulting in a high social burden. Due to recent advances in high-throughput sequencing technology, genetic studies identified more than 2500 genes associated with ID, and autosomal-recessive ID counts more than 50 % of the genetic causes of ID. A significant portion of ID cases shows an anatomical abnormality in the brain such as microcephaly and lissencephaly, suggesting a neurodevelopmental origin of the disorder. However, little is known about the molecular mechanisms underlying ID, which limits possible interventions and therapeutics of the disease. The goal of the project is to investigate the molecular mechanisms of ID using human-brain organoids. We have identified a group of ID-associated genes that encode proteins involved in RNA processing and modifications, and ID Patients with mutations in these genes have microcephaly. In this project, the function of those genes on cortical development will be investigated with the following specific objectives. Objective 1. To investigate the role of ID-associated genes in neural stem cell behaviour and neuronal migration and maturation in human forebrain organoids Objective 2. To determine transcriptomic changes upon genetic insults using single-cell RNA sequencing and identify target RNAs Objective 3. To identify the molecular mechanism of RNA processing involved in cortical development, and validate its functionality in cortical development The student will obtain fundamental concepts of brain development including neural stem cell behaviour and neuronal maturation during human cortical development and neurodevelopmental disorders. Technically, the student will learn how to culture human stem cells and brain organoids and assess neural development using immunohistochemistry, imaging, and computational analyses. Also, the student will have opportunities to learn molecular biology for genetic manipulation of ID genes and a biochemical approach to understand the RNA process