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.

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