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Deconstructing Reciprocal Genomic Disorders by Integration of Genome Engineering and Cellular Modeling

通过基因组工程和细胞建模的整合解构相互的基因组疾病

基本信息

批准号：
9470125
负责人：
Alexander Nuttle
金额：
$ 5.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-19 至 2019-09-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9470125
关键词：
16p11.2 Accounting Address Architecture Attention deficit hyperactivity disorder Autistic Disorder Biological Bipolar Disorder Cell Culture Techniques Cell Line Cell model Cells Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communities Copy Number Polymorphism Curiosities DNA Sequence Rearrangement Disease Disease model Engineering Environment Etiology Frequencies Gene Expression Gene Expression Profile Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genetic Variation Genome Genome engineering Genomic Segment Genomics Global Change Goals Human Human Genetics In Vitro Individual Intellectual functioning disability Light Link Meiosis Methods Modeling Molecular Molecular Profiling Morbidity - disease rate Mutation Nature Neurodevelopmental Disorder Neuronal Differentiation Neurons Neurosciences Overlapping Genes Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Patients Phenotype Process Recording of previous events Recurrence Research Research Personnel Risk Rosa Schizophrenia Series Specific qualifier value Symptoms Syndrome Technology Time Training Translating Work autism spectrum disorder disease phenotype dosage experimental study functional genomics genome editing homologous recombination induced pluripotent stem cell insight interest large scale production microdeletion nerve stem cell neurodevelopment neuropsychiatric disorder novel novel strategies post-doctoral training recombinase-mediated cassette exchange research and development stem cells synthetic biology therapeutic development transcriptome transcriptome sequencing transcriptomics

项目摘要

An important goal of human genomic research is the identification and characterization of genetic contributors to neurodevelopmental disease. Recurrent deletions and duplications of specific segments of our genome have emerged as some of the most common mutations identified in patients showing abnormal neurodevelopment. Collectively, these genomic losses and gains explain ~5-10% of autism spectrum disorder, schizophrenia, and intellectual disability. Despite intense interest in these rearrangements and their associated diseases, reciprocal genomic disorders (RGDs), relatively few studies have addressed their functional consequences at the molecular level. This project will leverage genome editing technology to generate a series of cell lines with deletions or duplications of interest against an isogenic background. RNA sequencing will then serve as a platform to investigate global changes in gene expression resulting from each rearrangement over the course of in vitro neuronal differentiation. First, I will establish, differentiate, and characterize cellular models for ten RGDs to describe and compare the transcriptional consequences of deletion and duplication at ten genomic intervals (Aim 1). Second, I will develop a method for parallel genome engineering and apply it to obtain cell lines with altered dosage of smaller segments and single genes within four RGD regions (Aim 2). Third, I will differentiate and characterize cell lines with these smaller rearrangements to identify genetic drivers underlying dysregulation observed in the four corresponding RGDs (Aim 3). This research will provide a detailed assessment and comparison of transcriptional effects of the most common RGD rearrangements. The parallel genome editing strategy will be made freely available to the scientific community, allowing researchers to generate hundreds or thousands of isogenic cell lines differing only by specified mutations of interest. Finally, genetic driver analyses promise to implicate new genes in the etiology of neurodevelopmental disease. Overall, by enhancing our molecular understanding of RGDs, this study will inform efforts to develop effective targeted treatments.

人类基因组研究的一个重要目标是鉴定和表征遗传贡献者