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： 躁郁症（BPD）是一种严重的精神障碍，对公共卫生有重大负担。 mirnas是 在大脑中高度表达，我们和其他人在BPD的神经病理学中发挥了作用 和其他精神疾病。但是，迄今 BPD被小样本量，较旧的检测平台和缺乏全面数据所阻碍 与其他基因组资源集成。 为了解决这些局限性，我们提出了一种翻译方法，将miRNA测序应用于 150例被诊断为躁郁症和 匹配的150个神经型对照，然后在100个匹配的独立样本中进行复制研究 案例/控制样本。我们的目标旨在充分利用这个临床上的大型且异常良好的优势 表征样品。有了我们的大量发现和复制样本，我们有能力确定适度的 通常在神经精神疾病中观察到的小效应大小。通过利用其他先前存在的基因组 我们的样本中生成的数据集（即GWAS数据和RNA-seq），我们将应用一系列的一系列。 这些基因组数据的全面整合的生物信息学和统计方法。这 集成将导致特定和可检验的假设的产生。例如，整合miRNA- 具有BPD的GWA（来自精神病基因组学联盟）的SEQ数据将揭示遗传机制 全基因组的显着风险变异有助于双相情感障碍的病因，例如变体 影响BPD病例和对照之间的miRNA表达。集成miRNA-seq和RNA-seq数据 将确定具有重要功能在双相情感障碍病因中的重要功能的miRNA基因靶标。最后，我们将确定 BPD的一组高置信风险miRNA（即，来自发现EQTL的MiRNA具有收敛证据， 生物信息学和复制分析）并在小鼠模型中传递这些分析，以描绘特定疾病的特定于 这些miRNA在BPD神经病理学中发挥作用和作用。 总之，与BPD相关的多态性的神经生物学机制增加了风险 对于躁郁症，未知。我们假设有助于神经病理学的一种机制 BPD是风险BPD变体影响miRNA表达的能力。使用如此大的发现和复制 BPD的大脑样本，我们将识别miRNA，其表达与躁郁症和 在控制BPD风险变异的控制下，并通过测试其对其对疾病的功能的进一步验证 小鼠模型的行为度量。