iPS Cell-Derived Neurons Carrying an allelic series of CNTNAP2 structural mutatio

携带 CNTNAP2 结构突变等位基因系列的 iPS 细胞衍生神经元

• 批准号: 7824631
• 负责人: JOSEPH A GOGOS
• 金额: $ 49.98万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7824631
• 关键词: Affect; Amish; Animal Model; Area; Autistic Disorder; Biological; Brain; Cell Line; Cells; Central Nervous System Diseases; Child; Communities; Coupled; Data; Derivation procedure; Disease; Disease model; Embryo; Engineering; Epilepsy; Etiology; Family; Gene Deletion; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genomics; Goals; Heterogeneity; Hippocampus (Brain); Human; In Vitro; Individual; Inherited; Institutes; International; Israel; Knock-out; Knockout Mice; Laboratories; Language; Lesion; Manuscripts; Mental Retardation; Mental disorders; Modeling; Mus; Mutation; Neurobiology; Neurodevelopmental Disorder; Neurons; Organism; Partial Epilepsies; Pathologic; Pathology; Patients; Penetrance; Phenotype; Probability; Property; Prosencephalon; Proteins; Recurrence; Relative (related person); Reporting; Research; Role; Schizophrenia; Schizophreniform Disorder; Series; Somatic Cell; Stem cells; Structure; Syndrome; System; Technology; Time; Tissues; Variant; Work; base; contactin; embryonic stem cell; experience; genetic risk factor; genetic variant; human data; human embryonic stem cell; in vivo; induced pluripotent stem cell; insight; interstitial; member; microdeletion; mouse model; neurodevelopment; neuropsychiatry; novel; public health relevance; relating to nervous system; specific language impairment; stem; stem cell technology; success; therapy development

DESCRIPTION (provided by applicant): Challenge Area: 14 --Stem Cells Challenge Topic: 14-MH-101*, "Developing iPS cells for mental disorders" The recent description of somatic cell reprogramming to an embryonic stem (ES) cell-like phenotype, termed induced pluripotent stem (iPS) cell technology, presents an exciting venue toward cell-based models of disease mutations. This technology affords for the first time the potential to analyze neuronal cells grown from individuals carrying a given genetic lesion and offers a unique way of direct assessment of pathology. Recent studies have established an important role for rare copy number variants (CNVs, genomic deletions and duplications) in the etiology of schizophrenia and autism. Rare, but recurrent CNVs affecting the CNTNAP2 gene, a member of the neurexin family, have been described in both disorders. Given the high penetrance and clearly delineated genomic structure, which offers clear clues regarding the underlying functional deficit, this CNV is ideal to model at the cellular level, as well as at the level of the organism. We propose to generate iPS cells and iPS cell- derived forebrain neurons from schizophrenic patients carrying variable size CNTNAP2 gene deletions and their unaffected relatives and undertake an initial characterization of their basic morphological and electrophysiological properties. A unique aspect of our proposal is that the proposed comparisons will use as a reference point data acquired both in vitro and in vivo from hippocampal and cortical neurons from an animal model genetically engineered to carry a Cntnap2 gene deletion. Cell lines generated from individuals with schizophrenia carrying specific well-defined structural mutations offer an unprecedented opportunity to recapitulate pathologic human neural tissue formation in vitro and provide a unique platform for studies aimed at both providing valuable insights into the disease mechanisms, and the potential discovery of new compounds to treat this devastating disorder. PUBLIC HEALTH RELEVANCE: There is considerable promise in generating induced pluripotent stem (iPS) cell lines from patients afflicted with central nervous system diseases, including psychiatric disorders. We propose to generate neurons from patients with schizophrenia carrying CNTNAP2 deletions, a genetic risk factor for the disease, study their properties and compare them to brain neurons of a knock/out mouse model of the same gene. This is an unprecedented opportunity for the field to combine data from human neurons carrying a bona fide genetic risk factor for schizophrenia and an established mouse model of the same genetic lesion.

描述（由申请人提供）：挑战领域：14 --干细胞挑战主题：14-MH-101*，“开发iPS细胞治疗精神障碍”最近描述的体细胞重编程为胚胎干（ES）细胞样表型，称为诱导多能干（iPS）细胞技术，提出了一个令人兴奋的场地对疾病突变的细胞为基础的模型。这项技术首次提供了分析从携带特定遗传病变的个体中生长的神经元细胞的潜力，并提供了一种直接评估病理的独特方法。最近的研究已经确定了罕见的拷贝数变异（CNVs，基因组缺失和重复）在精神分裂症和自闭症的病因学中的重要作用。在这两种疾病中，都描述了影响CNTNAP 2基因（neurexin家族的一个成员）的罕见但复发的CNV。鉴于高外显率和清晰描绘的基因组结构，这提供了有关潜在功能缺陷的明确线索，这种CNV是在细胞水平和生物体水平建模的理想选择。我们建议从携带不同大小CNTNAP 2基因缺失的精神分裂症患者及其未受影响的亲属中产生iPS细胞和iPS细胞衍生的前脑神经元，并对其基本形态学和电生理学特性进行初步表征。我们的建议的一个独特的方面是，所提出的比较将使用作为参考点的数据，在体外和体内从海马和皮层神经元从动物模型遗传工程携带Cntnap 2基因缺失。从携带特定明确结构突变的精神分裂症患者产生的细胞系提供了前所未有的机会，可以在体外重现病理性人类神经组织形成，并为旨在提供对疾病机制的有价值见解的研究提供了独特的平台，并可能发现新的化合物来治疗这种破坏性疾病。 公共卫生关系：从患有中枢神经系统疾病（包括精神障碍）的患者产生诱导多能干（iPS）细胞系有相当大的希望。我们建议从携带CNTNAP 2缺失的精神分裂症患者中产生神经元，CNTNAP 2缺失是该疾病的遗传风险因素，研究其特性并将其与相同基因的敲除小鼠模型的脑神经元进行比较。这是一个前所未有的机会，该领域结合联合收割机数据从人类神经元携带真正的遗传风险因素的精神分裂症和建立小鼠模型的相同遗传病变。