Assessing miRNA expression in the Corticolimbic System of Major Depressive Disorder

联系PD/PI：Vladimirov，弗拉基米尔I 摘要： 本研究的目的是探讨microRNA（miRNAs）在细胞内表达的生物学机制。 导致重度抑郁症（MDD）。抑郁症是一种严重的精神障碍，也是最常见的一种 自杀的危险因素。最近对MDD大样本的全基因组关联研究（GWAS）表明， 第一次发现了与重度抑郁症的强大遗传关联。然而，生物学机制， 这些因素会增加患抑郁症的风险，目前还不清楚。此外，大多数遗传变异 与MDD相关的基因落在蛋白质编码转录组之外，这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， 显示在精神疾病的病理学中起重要作用，包括MDD及其典型的 功能是控制基因表达水平。尽管它们很重要，但是， 在各种神经精神疾病的大型死后大脑样本中，包括不同大脑中的MDD 目前还不存在区域。 因此，在本申请中，我们建议使用miRNA测序来评估其中一种细胞中的miRNA表达。 世界上最大的重度抑郁症死后大脑样本该样本已被广泛 其特征在于临床，遗传和分子，并提供了一个独特的资源，检查 遗传因素直接导致原发性抑郁症的神经生物学机制 受影响的组织我们的miRNA数据将与正在进行的RNA测序数据整合， 受试者鉴定具有重要疾病功能的miRNA/mRNA对。我们的目标是：1）进行miRNA 对200例复发性MDD患者的膝下前扣带皮层（sACC）和杏仁核进行测序， 200名匹配的对照，2）测试来自MDD的GWAS的全基因组显著SNP是否与MDD的GWAS相关。 miRNA在大脑这些关键区域的表达，3）鉴定其表达与以下相关的miRNA： 严重抑郁症和自杀，并执行一系列的单变量，多变量（网络），和数据整合 分析以进一步阐明miRNA在MDD神经病理学中的作用，4）复制我们的顶级miRNA（FDR ≤5%） 在独立确定50例MDD病例和50例匹配对照的死后脑样本中。在目标4中，我们 还将进行一系列探索性分析，以确定风险MDD变异的细胞机制， 影响miRNA/mRNA相互作用。我们推测，一个主要的机制，有助于病因的主要 抑郁症是通过风险MDD变异体影响miRNA表达和功能的能力。通过解释 风险MDD变异导致重度抑郁症风险增加的机制，我们将提供新的 因此，它为疾病过程中的干预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.