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Role of L-type Calcium Channels in Human Interneuron Migration and Integration

L型钙通道在人中间神经元迁移和整合中的作用

基本信息

批准号：
9762226
负责人：
Sergiu Pasca
金额：
$ 58.67万
依托单位：
STANFORD UNIVERSITY
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：
2018-08-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762226
关键词：
3-Dimensional Actomyosin Bipolar Disorder Brain Brain region CRISPR/Cas technology Calcium Channel Calcium Signaling Cells Cerebral cortex Code Complex Defect Development Developmental Process Disease Dorsal Electrophysiology (science)Event Gene Expression Profile Gene Expression Profiling Gene Mutation Genes Genetic Genetic Engineering Genetic Risk Genetic Transcription Genetic study Glutamates Goals Guanosine Triphosphate Phosphohydrolases Human Human Engineering Hybrids Image In Vitro Interneurons L-Type Calcium Channels Label Lead Mental disorders Methods Molecular Morphology Mutation Neuraxis Neurodevelopmental Disorder Neurons Neurosciences Optics Organoids Patients Pattern Pharmacology Phenotype Play Positioning Attribute Process Prosencephalon Public Health Reporter Rodent Role Schizophrenia Signal Pathway Slice Stem cells Structure Synapses Technology Testing Timothy syndrome Transplantation Validation Variant Work autism spectrum disorder electrical property excitatory neuron experimental study gain of function mutation genetic variant genome wide association study in vivo induced pluripotent stem cell microphysiology system migration neural network neuropsychiatric disorder new therapeutic target next generation sequencing novel relating to nervous system risk variant single-cell RNA sequencing three dimensional cell culture voltage

项目摘要

ABSTRACT Gene variants and mutations in voltage-gated L-type calcium channels (LTCCs) genes are among the most replicable findings in genetic studies of autism spectrum disorders, bipolar disorder and schizophrenia. The mechanisms by which these genetic events lead to disease are not currently known. Previous work has indicated that these LTCss play a critical role in cortical interneuron migration and functional integration into cortical circuits. Here, we propose to leverage a novel tridimensional (3D) neural differentiation of human induced pluripotent stem cells (hiPSC) that we developed to generate functional neural spheroids resembling the laminated excitatory cerebral cortex (pallial spheroids) and, separately, subpallial spheroids giving rise to cortical interneurons. Using state-of-the-art live imaging, transcriptional profiling, genetic-engineering, pharmacology and electrophysiological methods, we plan to assemble two-region human forebrain structures (pallial-excitatory/subpallial-inhibitory) and investigate the functional role of LTCCs mutations in migration and functional synaptic integration of cortical interneurons. !

摘要