iPSC derived human cortical interneurons as developmental model of Schizophrenia

iPSC 衍生的人类皮质中间神经元作为精神分裂症的发育模型

• 批准号: 8944687
• 负责人: SANGMI CHUNG
• 金额: $ 47.4万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8944687
• 关键词: Address; Affect; Algorithms; Behavioral; Caucasians; Cells; Clozapine; Coculture Techniques; Code; Complement; Complex; Cultured Cells; Development; Disease; Environmental Risk Factor; Etiology; Exhibits; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic study; Genome; Genomics; Goals; Heritability; Human; Immune; Immune response; Immune system; Infection; Interneurons; Lead; Measurable Disease; Medial; Mendelian disorder; Microglia; Modeling; Molecular; Neurodevelopmental Disorder; Not Hispanic or Latino; Ontology; Pathogenesis; Pathologic Processes; Pathology; Pathway Analysis; Patients; Phase; Phenotype; Physiological; Population; Preclinical Drug Evaluation; Pregnancy; Preventive; Procedures; Property; Regulation; Research; Resistance; Resources; Risk; Risk Factors; Role; Sampling; Schizophrenia; Source; Specificity; Stress; Symptoms; System; Testing; Tissues; base; brain tissue; clinical phenotype; developmental disease; disease phenotype; gamma-Aminobutyric Acid; genome wide association study; genome-wide; immune activation; induced pluripotent stem cell; insight; male; neurodevelopment; new therapeutic target; novel; novel therapeutic intervention; postnatal; public health relevance; relating to nervous system; risk variant; therapeutic development; therapeutic target; tissue culture; transcriptome sequencing

 DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is a complex neurodevelopmental disorder with high heritability. Years of research show that SCZ is not a monogenic disease but a network disease with multiple risk genes and environmental factors of small effects interacting with each other to produce the clinical phenotype. The same risk factors can be implicated in multiple diseases, stressing the importance of studying SCZ in a network context. Our central hypothesis is that there are shared pathogenetic gene networks that underlie the complex and heterogeneous interactions of risk factors. Identification of such shared SCZ gene networks will be essential for identifying shared therapeutic targets. Remarkable advances have been made in recent genetic studies with an increasing number of risk gene loci reaching genome-wide significance. However, functional effects of many of these loci have not been elucidated due to their presence outside of the coding regions. Thus, developmental brain tissues from control and SCZ patients will be instrumental in clarifying their effects on gene expression during SCZ pathogenesis, leading to mechanistic insights into SCZ gene network and etiology. To this end, we have successfully optimized the differentiation of iPSCs into Medial Ganglionic Eminence (MGE)-type interneurons, which are one of the most consistently affected neural types in SCZ. Interestingly, our preliminary transcriptome analysis has shown that a significantly affected gene ontology term in developing SCZ MGE-type interneurons was the immune response, suggesting interactions between SCZ genomic burden and immune activation. In accordance with these findings, there were enriched SCZ associations among immune genes in a recent large-scale GWAS. Furthermore, maternal infection during pregnancy has been associated with SCZ and maternal immune activation models exhibit SCZ-like postnatal behavioral and histopathological abnormalities, including those in interneurons. Thus, employing highly homogeneous and well-characterized Sox6+GABA+ MGE-type interneurons from controls and SCZ iPSCs, we will test our hypothesis of shared SCZ gene networks during pathogenesis by analyzing common disturbances in SCZ transcriptome during neurodevelopment and their interactions with immune activation. To minimize controllable sources of variability, we will limit our subjects to non-Hispanic Caucasian males with severe disease phenotypes (treatment-resistant SCZ that required Clozapine treatment). Uncovering shared gene networks by various SCZ risk factors during development will provide novel and systemic insights into SCZ pathogenesis, complementing SCZ genetic studies by allowing analysis of tissue-specific modes of gene mis-expression. This will also lead to novel therapeutic targets for preventive treatments, which will address the primary pathologic processes rather than merely control symptoms.

 描述（由适用提供）：精神分裂症（SCZ）是一种复杂的神经发育障碍，具有较高的遗传力。多年的研究表明，SCZ不是一种是单基因疾病，而是一种具有多种风险基因的网络疾病，以及相互相互作用的小型环境因素以产生临床表型。可以在多种疾病中实施相同的风险因素，这强调了在网络环境中研究SCZ的重要性。我们的中心假设是，存在共同的致病基因网络，这些基因网络是危险因素复杂而异质相互作用的基础。识别此类共享SCZ基因网络对于识别共享的治疗靶标至关重要。在最近的遗传研究中取得了显着的进步，风险基因座的数量越来越多，具有全基因组意义。但是，由于它们在编码区域之外的存在，许多这些基因座的功能效应尚未阐明。这是从对照和SCZ患者中发展出脑组织的作用，将在SCZ发病机理期间对其对基因表达的影响发挥作用，从而导致对SCZ基因网络和病因的机械见解。为此，我们成功地优化了IPSC对介质神经节杰出（MGE）型中神经元的分化，该神经元是SCZ中最一致的神经类型之一。有趣的是，我们的初步转录组分析表明，在开发SCZ MGE型中间神经元中受到显着影响的基因本体论项是免疫响应，这表明SCZ基因组燃烧与免疫激活之间的相互作用。根据这些发现，在最近的大型GWAS中，免疫基因之间存在富集的SCZ关联。此外，怀孕期间的母体感染与SCZ有关，产妇免疫激活模型表现出SCZ样的产后行为和组织病理学异常，包括中间神经元。因此，通过对照和SCZ IPSC进行高度均匀且特征良好的SOX6+ GABA+ MGE型中神经元，我们将通过分析在神经发育过程中SCZ转录组中的常见灾害及其与免疫激活的相互作用，通过分析SCZ转录组中共享SCZ基因网络的假设。为了最大程度地减少受控的可变性来源，我们将把受试者限制在具有严重疾病表型（需要氯氮平治疗的耐药性SCZ）的非西班牙高加索男性中。开发过程中各种SCZ风险因素发现共享的基因网络将为SCZ发病机理提供新颖和全身的见解，从而通过允许分析基因错误表达的组织特异性模式来汇编SCZ遗传研究。这还将导致预防治疗的新型热靶标，这将解决主要的病理过程，而不仅仅是控制症状。