iPSC derived human cortical interneurons as developmental model of Schizophrenia

 描述（由申请人提供）：精神分裂症（SCZ）是一种复杂的神经发育障碍，具有高遗传性。多年的研究表明，SCZ不是一种单基因疾病，而是一种多个危险基因和影响较小的环境因素相互作用而产生临床表型的网络疾病。相同的风险因素可能涉及多种疾病，强调了在网络环境中研究SCZ的重要性。我们的中心假设是，有共同的致病基因网络的危险因素的复杂和异质性的相互作用的基础。鉴定这种共享的SCZ基因网络对于鉴定共享的治疗靶点是必不可少的。近年来遗传学研究取得了显著进展，越来越多的风险基因位点达到全基因组意义。然而，许多这些基因座的功能影响尚未阐明，由于它们的存在以外的编码区。因此，从控制和SCZ患者的发育脑组织将有助于澄清其对SCZ发病过程中的基因表达的影响，导致SCZ基因网络和病因机制的见解。为此，我们已经成功地优化了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，在开发SCZ MGE型中间神经元中，一个显著受影响的基因本体论术语是免疫应答，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，妊娠期间的母体感染与SCZ相关，母体免疫激活模型表现出SCZ样的出生后行为和组织病理学异常，包括中间神经元中的异常。因此，采用来自对照和SCZ iPSC的高度同质和充分表征的Sox6+GABA+ MGE型中间神经元，我们将通过分析神经发育期间SCZ转录组的常见干扰及其与免疫激活的相互作用来测试我们关于发病机制期间共享SCZ基因网络的假设。为了尽量减少可控的变异性来源，我们将受试者限制为具有重度疾病表型的非西班牙裔白人男性（需要氯氮平治疗的耐药SCZ）。揭示在发育过程中各种SCZ风险因素的共享基因网络将为SCZ发病机制提供新的和系统的见解，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靶点，这将解决主要的病理过程，而不仅仅是控制症状。

 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.