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.

抽象的： 双相情感障碍（BPD）是一种严重的精神障碍，给公众健康带来重大负担。 miRNA 是 在大脑中高度表达，我们和其他人已证明在 BPD 的神经病理学中发挥作用 和其他精神疾病。然而，迄今为止，所有发表的死后大脑 miRNA 表达研究 BPD 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，我们提出了一种将 miRNA 测序应用于 150 名双相情感障碍患者的杏仁核和膝下扣带皮层 (sAAC) 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复制研究 病例/对照样本。我们的目标是充分利用这个大型且异常良好的临床 特征样本。凭借我们的大量发现和复制样本，我们有能力识别中等到 通常在神经精神疾病中观察到的效应较小。通过利用其他预先存在的基因组 数据集（即 GWAS 数据和 RNA-seq）在我们的样本中生成，我们将应用一系列最先进的 用于全面整合这些基因组数据的生物信息和统计方法。这 整合将导致具体且可检验的假设的产生。作为一个例子，整合 miRNA- seq 数据与 BPD（来自精神病学基因组学联盟）的 GWAS 将揭示遗传机制 全基因组范围内的显着风险变异导致双相情感障碍的病因学，例如变异 影响 BPD 病例和对照之间 miRNA 的表达。整合 miRNA-Seq 和 RNA-Seq 数据 将鉴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，我们将识别 一组 BPD 的高置信度风险 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）并将其传递到小鼠模型中以描绘疾病特异性 这些 miRNA 在 BPD 神经病理学中发挥的功能和作用。 总之，与 BPD 相关的多态性增加风险的神经生物学机制 对于双相情感障碍尚不清楚。我们假设导致神经病理学的机制之一 BPD 的风险是 BPD 变异影响 miRNA 表达的能力。使用如此大规模的发现和复制 BPD 的大脑样本中，我们将鉴定 miRNA，其表达与双相情感障碍密切相关，并且 在 BPD 风险变异的控制下，并通过测试其对 BPD 的影响来进一步验证其疾病功能 小鼠模型中的行为测量。