Assessing miRNA expression in the Corticolimbic System of Major Depressive Disorder

评估重度抑郁症皮质边缘系统中的 miRNA 表达

• 批准号: 10810045
• 负责人: Vladimir Ivanov Vladimirov
• 金额: $ 45.13万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810045
• 关键词: Affect; Amygdaloid structure; Anterior; Autopsy; Biological; Biological Assay; Biology; Brain; Brain region; Clinical; Code; Collaborations; Collection; Data; Data Analyses; Data Discovery; Data Set; Development; Diagnosis; Disease; Etiology; Functional disorder; Gene Expression; Genetic; Genetic Risk; Genetic Transcription; Genotype; Goals; Intervention; Knowledge; Lead; Linear Regressions; Major Depressive Disorder; Mental disorders; Messenger RNA; MicroRNAs; Molecular; Morbidity - disease rate; National Institute of Mental Health; Nerve Degeneration; Neurobiology; Pathology; Patients; Phenotype; Play; Process; Proteins; Protocols documentation; Recording of previous events; Recurrence; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sample Size; Sampling; Series; Single Nucleotide Polymorphism; Substance abuse problem; Suicide; Suicide attempt; System; Testing; Time; Tissues; Universities; Variant; Virginia; cingulate cortex; data integration; disorder risk; effective therapy; falls; genetic association; genetic variant; genome wide association study; genome-wide; improved; insight; miRNA expression profiling; neurobiological mechanism; neurodevelopment; neuropathology; neuropsychiatric disorder; non-genetic; novel; pharmacologic; protein structure; risk variant; severe mental illness; synaptogenesis; trait; transcriptome; transcriptome sequencing; virtual; whole genome

Contact PD/PI: Vladimirov, Vladimir I Abstract: The objective of this proposal is to investigate the biological mechanisms by which microRNAs (miRNAs) contribute to major depressive disorder (MDD). MDD is a severe mental disorder and the single most common risk factor for suicide. Recent genome-wide association studies (GWAS) of large samples of MDD have for the first time identified robust genetic associations with major depression. However, the biological mechanisms by which these increase the risk for major depression are still unknown. Additionally, most genetic variants associated with MDD fall outside of the protein coding transcriptome, suggesting that their functional impact is likely to affect gene expression levels rather than protein structure. MiRNA are highly expressed in the brain and were shown to play an important role in the pathology of psychiatric disorders including MDD and their canonical functions are to control gene expression levels. Despite their importance, however, profiling of miRNA expression in large postmortem brain samples for various neuropsychiatric disorders including MDD across different brain regions currently do not yet exist. Thus, in this application we propose to use miRNA sequencing to assess miRNA expression in one of the largest postmortem brain samples of major depression in the world. The sample has been extensively characterized clinically, genetically, and molecularly and provides a unique resource for examining the neurobiological mechanisms by which genetic factors contribute to major depression directly in the primary affected tissue. Our miRNA data will be integrated with an ongoing RNA sequencing data generated in the same subjects to identify miRNA/mRNA pairs with important disease functions. Our aims are to: 1) carry out miRNA sequencing of the subgenual anterior cingulate cortex (sACC) and amygdala in 200 recurrent MDD cases and 200 matched controls, 2) test whether genome-wide significant SNPs from GWAS of MDD are associated with miRNA expression across these key regions of the brain, 3) identify miRNA whose expression is associated with major depression and suicide and perform a series of univariate, multivariate (network), and data integration analyses to further elucidate miRNA role in the neuropathology of MDD, 4) replicate our top miRNA (FDR ≤5%) in an independently ascertain postmortem brain sample of 50 MDD cases and 50 matched controls. In aim 4 we will also perform series of exploratory analyses to identify the cellular mechanism by which risk MDD variants affect miRNA/mRNA interactions. We hypothesize that a major mechanism contributing to the etiology of major depression is through the ability of risk MDD variants to affect miRNA expression and functions. By explicating the mechanisms by which risk MDD variants lead to increase risk of major depression, we will provide novel targets for intervention in the disease process and, therefore, a more rational basis for improved treatments.

联系PD/PI：Vladimirov，Vladimir I 抽象的： 该建议的目的是研究microRNA（miRNA）的生物学机制 有助于重大抑郁症（MDD）。 MDD是一种严重的精神障碍，是最常见的 自杀的危险因素。 MDD大型样本的最近全基因组关联研究（GWAS）具有 第一次确定了与重度抑郁症的强大遗传关联。但是，生物学机制 这会增加严重抑郁症的风险。另外，大多数遗传变异 与MDD相关的属于蛋白质编码转录组之外，表明它们的功能影响是 可能影响基因表达水平而不是蛋白质结构。 miRNA在大脑中高度表达， 我们被证明在包括MDD在内的精神疾病的病理学中起着重要作用 功能是控制基因表达水平。尽管它们的重要性，但miRNA表达的分析 在大型神经精神疾病（包括MDD）的大脑大脑样本中 目前尚不存在地区。 在此应用中，我们建议使用miRNA测序来评估其中一个中的miRNA表达 世界上最大的尸体后大脑样本。样本已广泛 在临床，一般和分子上表征 遗传因素直接导致重大抑郁症的神经生物学机制 影响组织。我们的miRNA数据将与正在进行的RNA测序数据集成在一起 受试者鉴定具有重要疾病功能的miRNA/mRNA对。我们的目标是：1）执行mirna 在200例复发性MDD病例中，亚属前扣带回皮质（SACC）和杏仁核的测序 200个匹配的对照，2）测试MDD GWA的全基因组明显SNP是否与 miRNA在大脑的这些关键区域之间 重大抑郁和自杀并执行一系列单变量，多变量（网络）和数据集成 分析以进一步阐明MIRNA在MDD的神经病理学中的作用，4）复制我们的顶部miRNA（FDR≤5％） 在独立确定的50例MDD病例和50个匹配对照的死后大脑样本中。在目标4中我们 还将执行一系列探索性分析，以确定风险MDD变体的细胞机制 影响miRNA/mRNA相互作用。我们假设有助于主要的病因的主要机制 抑郁是通过风险MDD变体影响miRNA表达和功能的能力。通过解释 风险MDD变体导致增加严重抑郁症的风险的机制，我们将提供新颖 干预疾病过程的目标，因此是改进治疗方法的更合理基础。