Translational Approach to Studying miRNA functions in sACC and amygdala in patients with BPD

研究 BPD 患者 sACC 和杏仁核 miRNA 功能的转化方法

• 批准号: 10635583
• 负责人: Vladimir Ivanov Vladimirov
• 金额: $ 63.15万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635583
• 关键词: Address; Affect; Age of Onset; Amygdaloid structure; Anhedonia; Anterior; Anxiety; Autopsy; Behavior; Behavioral; Bioinformatics; Biological; Bipolar Disorder; Blood Pressure; Body Temperature; Brain; Brain region; Clinical; Data; Data Set; Diagnosis; Disease; Electrocardiogram; Etiology; Functional disorder; Gene Targeting; Generations; Genetic; Genetic Polymorphism; Genomics; Genotype; Goals; Heart Rate; Hyperactivity; Injections; Knowledge; Limbic System; Lithium; Measures; Mental Depression; Mental disorders; MicroRNAs; Molecular; Mood stabilizers; Mus; Nerve Degeneration; Neurobiology; Patients; Phenotype; Physiological; Physiology; Play; Prevalence; Protocols documentation; Public Health; Publishing; Quantitative Trait Loci; Research; Risk; Rodent; Role; Sample Size; Sampling; Science; Secondary to; Series; Signal Transduction; Teenagers; Testing; United States National Institutes of Health; Validation; Variant; Work; anti social; behavior measurement; behavioral study; brain tissue; cingulate cortex; cost; cost effective; data integration; design; detection platform; differential expression; disorder risk; experience; genetic architecture; genetic association; genetic variant; genome resource; genome wide association study; genome-wide; genomic data; miRNA expression profiling; mouse model; neurobiological mechanism; neuropathology; neuropsychiatric disorder; psychiatric genomics; risk variant; severe mental illness; skills; transcriptome sequencing; translational approach

Abstract: Bipolar disorder (BPD) is a severe mental disorder with a significant burden on public health. MiRNAs are highly expressed in the brain and have been shown by us and others to play a role in the neuropathology of BPD and other psychiatric disorders. However, to date, all published postmortem brain miRNA expression studies of BPD have been hampered by small sample sizes, older detection platforms, and a lack of comprehensive data integration with other genomic resources. To address these limitations, we propose a translational approach that will apply miRNA sequencing in the amygdala and subgenual cingulate anterior cortex (sAAC) in 150 patients diagnosed with bipolar disorder and matched 150 neurotypical controls, followed by a replication study in an independent sample of 100 matched case/control sample. Our aims are designed to take full advantage of this large and exceptionally well clinically characterized sample. With our large discovery and replication samples, we are powered to identify moderate to small effect sizes typically observed in neuropsychiatric disorders. By leveraging other pre-existing genomic datasets (i.e., GWAS data and RNA-seq) generated in our sample, we will apply a state-of-art series of bioinformatic and statistical approaches for the comprehensive integration of these genomic data. This integration will lead to the generation of specific and testable hypotheses. As an example, integrating the miRNA- seq data with GWAS of BPD (from the Psychiatric Genomics Consortium) will reveal the genetic mechanisms by which genome-wide significant risk variants contribute to the etiology of bipolar disorder, e.g., variants affecting miRNA expression between BPD cases and controls. Integrating the miRNA-Seq and RNA-Seq data will identify miRNA gene targets with important functions in the etiology of bipolar disorder. Finally, we will identify a set of high confidence risk miRNA of BPD (i.e., miRNAs with convergent evidence from the discovery, eQTL, bioinformatic, and replication analyses) and deliver these in mice models to delineate the disease-specific functions and roles these miRNA play in BPD neuropathology. In summary, the neurobiological mechanisms by which polymorphisms associated with BPD increase the risk for bipolar disorder are unknown. We hypothesize that one of the mechanisms contributing to the neuropathology of BPD is the ability of risk BPD variants to affect miRNA expression. Using such large discovery and replication brain samples of BPD, we will identify miRNA, whose expression is robustly associated with bipolar disorder and under the control of risk variants for BPD and further validate their disease functions by testing their impact on behavioral measures in mice models.

摘要： 双相情感障碍(BPD)是一种严重的精神障碍，对公众健康造成重大负担。MiRNAs是 在大脑中高度表达，并已被我们和其他人证明在BPD的神经病理中发挥作用 以及其他精神疾病。然而，到目前为止，所有已发表的死后脑miRNA表达研究 BPD一直受到样本量小、检测平台陈旧和缺乏全面数据的阻碍 与其他基因组资源的整合。 为了解决这些限制，我们提出了一种翻译方法，将miRNA测序应用于 150例双相情感障碍患者杏仁核和扣带回前皮质 匹配150个神经典型对照，然后在100个匹配的独立样本中进行重复研究 病例/对照样本。我们的目标是充分利用这一巨大的和特别好的临床 已表征的样品。通过我们的大量发现和复制样本，我们能够识别出中等到 通常在神经精神障碍中观察到的小效应量。通过利用其他预先存在的基因组 在我们的样本中生成的数据集(即Gwas数据和RNA-seq)，我们将应用一系列最先进的 全面整合这些基因组数据的生物信息学和统计学方法。这 整合将导致具体和可检验的假说的产生。例如，将miRNA- BPD(精神病学基因组学联盟)的GWASEQ数据将揭示遗传机制 全基因组范围内的显著风险变异对双相情感障碍的病因有贡献，例如，变异 在BPD病例和对照组之间影响miRNA的表达。整合miRNA-Seq和RNA-Seq数据 将确定在双相情感障碍病因学中具有重要功能的miRNA基因靶点。最后，我们将确定 BPD的一组高置信度风险miRNA(即，具有来自发现的收敛证据的miRNA，eQTL， 生物信息学和复制分析)，并在小鼠模型中提供这些信息，以描述疾病特异性 这些miRNA在BPD神经病理中的功能和作用。 综上所述，与BPD相关的多态增加风险的神经生物学机制 对双相情感障碍的治疗尚不清楚。我们推测，导致神经病理的机制之一 BPD的关键是有风险的BPD变体影响miRNA表达的能力。使用如此大规模的发现和复制 BPD的大脑样本，我们将识别miRNA，其表达与双相情感障碍和 在BPD风险变量的控制下，通过测试它们对BPD的影响来进一步验证它们的疾病功能 小鼠模型的行为学测量。