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（由申请人提供）：精神分裂症（SCZ）是一种具有高度遗传性的复杂神经发育障碍。多年研究表明，SCZ不是单基因疾病，而是多种危险基因和影响较小的环境因素相互作用产生临床表型的网络疾病。相同的危险因素可能与多种疾病有关，这强调了在网络背景下研究 SCZ 的重要性。我们的中心假设是，危险因素复杂且异质的相互作用背后存在着共同的致病基因网络。识别这种共享的 SCZ 基因网络对于识别共享的治疗靶点至关重要。最近的遗传学研究取得了显着的进展，越来越多的风险基因位点达到了全基因组的重要性。然而，由于这些基因座存在于编码区之外，因此许多基因座的功能效应尚未阐明。因此，对照和 SCZ 患者的发育脑组织将有助于阐明其对 SCZ 发病机制期间基因表达的影响，从而对 SCZ 基因网络和病因学产生机制性见解。为此，我们成功优化了 iPSC 向内侧神经节隆起 (MGE) 型中间神经元的分化，这是 SCZ 中最一致受影响的神经类型之一。有趣的是，我们的初步转录组分析表明，在 SCZ MGE 型中间神经元发育中受到显着影响的基因本体术语是免疫反应，这表明 SCZ 基因组负荷和免疫激活之间存在相互作用。根据这些发现，在最近的大规模 GWAS 中，免疫基因之间存在丰富的 SCZ 关联。此外，孕期母体感染与 SCZ 相关，母体免疫激活模型表现出类似 SCZ 的产后行为和组织病理学异常，包括中间神经元的异常。因此，利用来自对照和 SCZ iPSC 的高度同质且特征良好的 Sox6+GABA+ MGE 型中间神经元，我们将通过分析神经发育过程中 SCZ 转录组的常见干扰及其与免疫激活的相互作用来检验我们在发病机制中共享 SCZ 基因网络的假设。为了最大限度地减少可控变异源，我们将受试者限制为具有严重疾病表型的非西班牙裔白人男性（需要氯氮平治疗的耐药性 SCZ）。揭示发育过程中各种 SCZ 风险因素的共享基因网络将为 SCZ 发病机制提供新颖和系统的见解，通过允许分析基因错误表达的组织特异性模式来补充 SCZ 遗传研究。这也将为预防性治疗带来新的治疗目标，这将解决主要病理过程，而不仅仅是控制症状。