Assessing miRNA expression in the Corticolimbic System of Major Depressive Disorder

联系PD/PI：弗拉基米罗夫，弗拉基米尔一世 摘要： 这项建议的目的是研究microRNAs(MiRNAs) 导致严重抑郁障碍(MDD)。MDD是一种严重的精神障碍，也是最常见的 自杀的危险因素。最近对MDD大样本的全基因组关联研究(GWAS)已经为 第一次确定了基因与严重抑郁症之间的密切联系。然而，生物机制通过 其中哪些因素会增加患严重抑郁症的风险仍是未知之数。此外，大多数遗传变异 与MDD相关的基因位于蛋白质编码转录组之外，这表明它们的功能影响是 可能会影响基因表达水平，而不是蛋白质结构。MiRNA在大脑中高度表达， 被证明在包括MDD及其典型的精神疾病的病理学中起着重要作用 其功能是控制基因表达水平。然而，尽管它们很重要，但miRNA表达的图谱 在大量死后大脑样本中检测各种神经精神疾病，包括跨不同大脑的MDD 地区目前还不存在。 因此，在本应用中，我们建议使用miRNA测序来评估miRNA在其中一个 世界上最大的抑郁症死后大脑样本。样本已经被广泛地 在临床上、遗传学上和分子上具有特征，并为检查 遗传因素直接导致原发性抑郁症的神经生物学机制 受影响组织。我们的miRNA数据将与正在进行的RNA测序数据整合在一起 受试者识别具有重要疾病功能的miRNA/mrna对。我们的目标是：1)进行miRNA 200例复发MDD患者的扣带回前皮质和杏仁核序列分析 200名配对对照，2)测试来自MDD患者GWAs的全基因组显著SNP是否与 MiRNA在大脑这些关键区域的表达，3)确定其表达与 严重抑郁和自杀，并进行一系列单变量、多变量(网络)和数据整合 分析进一步阐明miRNA在MDD神经病理中的作用，4)复制我们最高的miRNA(FDR≤5%) 在一项独立确定的50例MDD患者和50名匹配对照的死后脑样本中。在Aim 4中，我们 还将进行一系列探索性分析，以确定MDD变异风险的细胞机制 影响miRNA/mRNA的相互作用。我们假设，导致重大疾病的主要机制是 抑郁症是通过MDD高危变种影响miRNA表达和功能的能力造成的。通过解释 风险MDD变异导致严重抑郁症风险增加的机制，我们将提供新的 为疾病进程的干预提供了目标，从而为改进治疗提供了更合理的基础。

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.