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严重受限为特征的疾病，在成年前发病。全世界有1%-2%的儿童患有该病，造成了很高的社会负担。由于最近高通量测序技术的进步，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。很大一部分ID病例显示出大脑的解剖异常，如小头畸形和小脑畸形，提示该疾病的神经发育起源。然而，人们对ID的分子机制知之甚少，这限制了对该疾病的可能干预和治疗。该项目的目标是利用人脑有机化合物研究ID的分子机制。我们已经确定了一组与ID相关的基因，这些基因编码参与RNA处理和修饰的蛋白质，这些基因突变的ID患者患有小头畸形。在这个项目中，这些基因在皮质发育中的功能将以下列特定的目标进行研究。目的1.研究ID相关基因在人类前脑器官中神经干细胞行为和神经元迁移与成熟中的作用目标2.利用单细胞RNA测序技术确定遗传损伤后转录水平的变化，并确定靶RNA。目的3.为了确定参与皮质发育的RNA加工的分子机制，并验证其在皮质发育中的功能，学生将获得脑发育的基本概念，包括人类皮质发育和神经发育障碍期间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，学生还将有机会学习ID基因的遗传操作的分子生物学，以及了解RNA过程的生化方法

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