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Collaboration on preclinical autism cellular assays, biosignatures, and network analyses (Copacabana)

临床前自闭症细胞检测、生物特征和网络分析方面的合作（Copacabana）

基本信息

批准号：
8935692
负责人：
Eugene Wei-Ming Yeo
金额：
$ 280.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8935692
关键词：
Adoption Astrocytes Autistic Disorder Biological Assay Biology Brain Brain Diseases Cell Line Cell Therapy Cell model Cells Cellular Assay Collaborations Complex Computational Biology Data Set Development Diagnostic Diagnostic Procedure Disease Disease model Dissection Drug Targeting Engineering Event Functional disorder Genetic Genetic Engineering Genetic Models Genetic Transcription Genome engineering Genomics Haplotypes Helper Viruses Heterogeneity Human Image Analysis In Vitro Individual Institutes Label Laboratories Measures Medicine Mental Health Methods Modeling Molecular Molecular Profiling Mus Neurites Neuroglia Neurons Neurosciences Normal Cell Patients Phenotype Preclinical Drug Evaluation Process Proteins Protocols documentation RNA Rabies virus Research Resources Stem cells Symptoms Synapses Technology Testing Variant autism spectrum disorder base biosignature cell type density drug discovery genetic variant genome editing imaging modality improved induced pluripotent stem cell inhibitory neuron innovation insight mutant nervous system disorder neural circuit novel novel diagnostics pre-clinical pre-clinical research protein expression public health relevance public-private partnership screening stem cell biology synaptogenesis tool

项目摘要

DESCRIPTION (provided by applicant): This study aims to generate robust tools and workflows for creating human induced pluripotent stem cell (hIPSC)-based models of autism spectrum disorder (ASD), and to develop scalable assays for predictive molecular and cellular phenotypes relevant to autism. We have identified several key bottlenecks in the widespread adoption of hIPSCs as tools that allow the dissection of molecular mechanisms underlying neurological disease and enable preclinical drug screening. We have assembled a team of five leading experts in neuroscience, stem cell biology and computational biology, who will collaborate up with three innovation-driven biotech companies (Fluidigm, BD Biosciences and Synthetic Genomics) to overcome these roadblocks. Since autism is considered a disorder of synapse development and function that ultimately leads to circuit dysfunction in the brain, we will develop quantitative assays of synapse end network function that can be used in high-throughput drug screens. We also aim to uncover the upstream molecular events that precipitate synaptic and network dysregulation, and identify predictive RNA and protein signatures. Our strategy is to engineer models of genetic forms of autism by genomic manipulation using a well- characterized, neurotypical hIPSC line as the starting point. We will then differentiate these normal and mutant cells to cortical neurons and astrocytes, the two cell types that have been most strongly implicated in autism pathophysiology. Highly quantitative and sensitive assays at the single-cell level will be used to identify changes in protein and RNA expression that can distinguish ASD neurons and astrocytes from normal cells. Finally, we will develop assays measuring synapse density and strength using advanced technology that can be used in high-throughput format. We envision that our tools, technologies and assays, all of which we will make publicly available as they are being generated, will both critically contribute to our understanding of ASD and accelerate preclinical research of neurological disease.