Cellular and molecular mechanisms disrupted in 22q13 deletion syndrome and autism

22q13 缺失综合征和自闭症的细胞和分子机制被破坏

基本信息

批准号：
10326382
负责人：
Oleksandr Shcheglovitov
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326382
关键词：
AMPA Receptors Address Affect Alleles Astrocytes Back Basic Science Behavioral Binding Biochemistry Brain Cell Line Chronic Complex Cytoskeleton Data Defect Development Electrophysiology (science)Endocytosis Engraftment Etiology Excitatory Synapse Financial compensation Functional disorder Gene Expression Genes Genetic Genetic Engineering Genetic Suppression Goals HCN1 gene Human Image Impairment In Vitro Induced pluripotent stem cell derived neurons Intellectual functioning disability Knock-out Laboratories Lead Measures Mediating Membrane Mental disorders Mission Modeling Molecular Molecular Abnormality Mus Mutate Mutation National Institute of Mental Health Neurodevelopmental Disorder Neurons Pathology Patients Pharmacology Phelan-McDermid syndrome Phenotype Prefrontal Cortex Property Proteins Public Health Reporting Research Research Project Grants Resistance Rodent Role Scaffolding Protein Synapses Synaptic Transmission Syndrome Techniques Technology Testing Translations Up-Regulation autism spectrum disorder brain abnormalities engineered stem cells experimental study functional disability improved in vivo individuals with autism spectrum disorder induced pluripotent stem cell insight knock-down neural network novel novel therapeutic intervention novel therapeutics therapeutically effective

项目摘要

Mutations in genes encoding synaptic proteins and impaired functional brain connectivity are emerging as common deficits associated with autism spectrum disorders (ASDs). However, how mutated synaptic proteins affect the properties of human neurons at the cellular and molecular levels to cause abnormal brain connections remains an important unanswered question. Addressing this question is essential for understanding the etiology and pathology of ASDs and developing novel and effective therapeutic strategies for patients. The PI previously demonstrated that SHANK3-deficient human cortical neurons derived from induced pluripotent stem cells (iPSCs), generated from 22q13 deletion syndrome patients with autism, have severely impaired intrinsic excitability and excitatory synaptic transmission. However, how these two phenotypes develop and affect neuronal connectivity in the brain remain unknown. The main goal of this project is to elucidate the cellular and molecular mechanisms responsible for development of synaptic and connectivity deficits in SHANK3-deficient human neurons. SHANK3 is a scaffolding protein expressed at excitatory synapses that have been frequently found to be mutated or deleted in individuals with autism and intellectual disability. The central hypothesis of this project is that synaptic deficits in SHANK3-deficient human neurons develop as a result of elevated electrical activity and activity-mediated weakening and elimination of excitatory synapses. This hypothesis is strongly supported by the preliminary data obtained in the PI's laboratory. The following Specific Aims are formulated to test this hypothesis: 1) Determine the role of elevated electrical activity in development of synaptic deficits in SHANK3-deficient human neurons; 2) Determine the role of ARC in development of synaptic deficits in SHANK3-deficient human neurons; and 3) Determine how loss of SHANK3 in human neurons impacts synaptic inputs onto these neurons in vivo. Under these aims, the properties of human cortical neurons generated from novel, precisely genetically-engineered stem cell lines will be investigated using electrophysiology, imaging, and biochemistry techniques in vitro and upon engraftment into the mouse brain. The proposed research is significant because it is expected to substantially advance understanding of the molecular, cellular, and circuitry mechanisms disrupted in autism and intellectual disability, and guide the development of novel therapeutic strategies for patients.

编码突触蛋白的基因突变和大脑功能连接受损正在出现作为与自闭症谱系障碍 (ASD) 相关的常见缺陷。然而，突触如何突变蛋白质在细胞和分子水平上影响人类神经元的特性，导致大脑异常连接仍然是一个重要的悬而未决的问题。解决这个问题至关重要了解自闭症谱系障碍的病因和病理学并制定新颖有效的治疗策略对于患者。 PI 之前证明，SHANK3 缺陷的人类皮质神经元源自诱导多能干细胞（iPSC）是从患有自闭症的 22q13 缺失综合征患者中产生的内在兴奋性和兴奋性突触传递严重受损。然而，这两个如何表型的发展和对大脑神经元连接的影响仍然未知。此次活动的主要目标该项目旨在阐明负责突触和突触发育的细胞和分子机制 SHANK3 缺陷的人类神经元的连接缺陷。 SHANK3 是一种支架蛋白，表达于经常发现自闭症患者的兴奋性突触发生突变或删除智力障碍。该项目的中心假设是 SHANK3 缺陷人类的突触缺陷神经元的发育是电活动升高和活动介导的弱化和消除的结果兴奋性突触。这一假设得到 PI 中获得的初步数据的有力支持实验室。制定以下具体目标来检验这一假设： 1) 确定升高的作用 SHANK3 缺陷的人类神经元突触缺陷发展中的电活动； 2）确定 ARC 在 SHANK3 缺陷的人类神经元突触缺陷发展中的作用； 3) 确定如何人类神经元中 SHANK3 的缺失会影响体内这些神经元的突触输入。在这些目标下，由新颖的、精确的基因工程干细胞系产生的人类皮质神经元的特性将在体外和植入后使用电生理学、成像和生物化学技术进行研究进入小鼠大脑。拟议的研究意义重大，因为预计它将大大推进对自闭症和智力障碍的分子、细胞和电路机制的理解残疾，并指导为患者制定新的治疗策略。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Probing disrupted neurodevelopment in autism using human stem cell-derived neurons and organoids: An outlook into future diagnostics and drug development.

DOI：
10.1002/dvdy.100
发表时间：
2020-01
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
0
作者：
Yang G;Shcheglovitov A
通讯作者：
Shcheglovitov A

Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes.