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.

编码突触蛋白和功能性脑连接受损的基因突变正在出现作为与自闭症谱系障碍（ASD）相关的常见缺陷。但是，如何突变蛋白质会影响人类神经元在细胞和分子水平上的特性，从而引起脑异常联系仍然是一个重要的未解决问题。解决这个问题对于了解ASD的病因和病理学，并制定新颖有效的治疗策略适用于患者。 PI先前证明了Shank3缺陷的人皮质神经元诱导多能干细胞（IPSC），由22q13缺失综合症患者自闭症患者产生内在兴奋性和兴奋性突触传播严重受损。但是，这两个如何表型发展并影响大脑的神经元连通性仍然未知。主要目标项目是为了阐明负责突触发展的细胞和分子机制 Shank3缺陷的人类神经元中的连通性缺陷。 shank3是一种表达的脚手架蛋白经常发现在自闭症患者和智力残疾。该项目的中心假设是Shank3缺陷人类的突触缺陷神经元由于电活动升高和活性介导的弱化和消除而发展兴奋性突触。该假设得到了PI中获得的初步数据的强烈支持实验室。提出以下特定目的以检验以下假设：1）确定升高的作用尚克3缺陷人神经元突触缺陷发育中的电活动； 2）确定 ARC在不足的人类神经元中突触缺陷发展中的作用； 3）确定如何人神经元中尚克3的丧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，精确的遗传学干细胞系产生的人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。拟议的研究很重要，因为它有望大大提高对自闭症和智力中破坏的分子，细胞和电路机制的理解残疾，并指导针对患者的新型治疗策略的发展。

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.