The schizophrenia candidate gene MIR137: functional studies in mouse

精神分裂症候选基因MIR137：小鼠功能研究

• 批准号: 8876802
• 负责人: PATRICK F SULLIVAN
• 金额: $ 19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876802
• 关键词: Address; Alzheimer' s Disease; Behavior; Behavioral; Binding; Biological; Biological Process; Biology; Brain; Candidate Disease Gene; Cells; Complex; Data; Data Analyses; Defect; Development; Disease; Etiology; Evaluation; Female; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Health; Heritability; Hippocampus (Brain); Human; Huntington Disease; Immunoprecipitation; Individual; Intellectual functioning disability; Knowledge; Link; Measures; Methods; MicroRNAs; Morbidity - disease rate; Mus; Neurologic; Neuronal Differentiation; Neurons; Pathogenesis; Pathway interactions; Pattern; Phenotype; Play; Prevalence; Process; Quality of life; RNA; RNA Binding; RNA Degradation; Regulation; Reporting; Risk; Risk Factors; Role; Schizophrenia; Site; Structure; Sweden; Testing; Time; Transcript; Translational Repression; base; brain size; density; exome sequencing; gene function; genetic risk factor; genome wide association study; genome-wide; innovation; mRNA Transcript Degradation; male; mouse model; nervous system disorder; neurodevelopment; neurogenesis; neuron development; novel; research study; transcriptome sequencing

DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is a complex and often devastating disease with a lifetime prevalence of 0.4%7 and heritability of ~80%.8 It is widely believed to be of neurodevelopmental origin.9, 10 There is now strong genetic evidence implicating the gene MIR137 and its microRNA (miRNA) product miR-137 in the etiology of SCZ. Association with this region has now reached 1.7x10-12 (N=59,318).1 14 genes have predicted or confirmed miR-137 target sites and genes with predicted miR-137 targets were significantly enriched for small GWAS p- values (p<0.01). In addition, miR-137 is implicated in neurodevelopment, Alzheimer's disease2, intellectual disability3, Huntington's disease,4 and mouse models of Rett syndrome.5 Therefore, miR-137 is a miRNA of important biological function and an intriguing candidate in SCZ and other neurological disease. We therefore propose to test the hypothesis that miR-137 is important for neuronal development in the mouse, identify pathways regulated by miR-137, and test whether these pathways play a role in the pathogenesis of SCZ. Using mice in which the Mir137 gene has been deleted, we will first characterize the mice for neurological or behavioral deficits. To address the role of miR-137 in proliferation and differentiation of neuronal cells, we will evaluate brain size and structure, neuronal density, neurogenesis, and dendritic complexity. miRNAs are known to directly regulate other RNAs through targeting for degradation or translational inhibition. Therefore, we will use an innovative combination of RNAseq and PAR-CLIP (an immunoprecipitation based method to identify RNAs bound by the miRNA regulation complex) to identify both direct and indirect targets of miR-137 in mouse brain. We will analyze these data to identify individual genes and biological pathways or networks influenced by miR-137. Finally, we will address whether the pathways and networks regulated by miR-137 are disrupted in SCZ by comparing to results from existing SCZ GWAS (PGC, >31,000 cases), exome sequencing (Sweden, 2500 cases), and post-mortem gene expression studies. These experiments will evaluate the role of miR-137 in the mouse brain, identify potential targets of miR-137 (both primary and secondary), and test for dysregulation of the miR-137 controlled pathway in SCZ. These results could provide functional evidence in support of a highly significant common risk factor for SCZ.

描述（由申请人提供）：精神分裂症（SCZ）是一种复杂且通常具有破坏性的疾病，终生患病率为0.4%7，遗传率约为80%。8人们普遍认为其起源于神经发育。9，10目前有强有力的遗传学证据表明基因MIR 137及其microRNA（miRNA）产物miR-137与SCZ的病因有关。与该区域的关联现在已经达到1.7x10-12（N= 59，318）。114个基因已经预测或确认了miR-137靶位点，并且具有预测的miR-137靶的基因对于小的GWAS p值显著富集（p<0.01）。此外，miR-137还与神经发育、阿尔茨海默病2、智力残疾3、亨廷顿病4和Rett综合征小鼠模型5有关。因此，miR-137是一种具有重要生物学功能的miRNA，是SCZ和其他神经系统疾病中一个有趣的候选者。因此，我们建议验证miR-137对小鼠神经元发育很重要的假设，确定miR-137调控的途径，并测试这些途径是否在SCZ的发病机制中发挥作用。使用Mir 137基因已被删除的小鼠，我们将首先表征小鼠的神经或行为缺陷。为了解决miR-137在神经元细胞增殖和分化中的作用，我们将评估大脑的大小和结构，神经元密度，神经发生和树突的复杂性。已知miRNA通过靶向降解或翻译抑制直接调节其他RNA。因此，我们将使用RNAseq和PAR-CLIP（一种基于免疫沉淀的方法，用于识别miRNA调控复合物结合的RNA）的创新组合来识别小鼠大脑中miR-137的直接和间接靶标。我们将分析这些数据，以确定受miR-137影响的单个基因和生物学途径或网络。最后，我们将通过与现有SCZ GWAS（PGC，> 31，000例），外显子组测序（瑞典，2500例）和死后基因表达研究的结果进行比较，来解决由miR-137调控的途径和网络是否在SCZ中被破坏。这些实验将评估miR-137在小鼠脑中的作用，鉴定miR-137的潜在靶点（主要和次要），并测试SCZ中miR-137控制途径的失调。这些结果可以提供功能性证据，支持SCZ的一个非常重要的共同危险因素。