microRNA Expression Patterns in Human Psychiatric CNS Samples

描述(由申请人提供)：情绪障碍是一类对个人、家庭、社区、雇主和医疗保健系统有深远影响的破坏性疾病。虽然有许多药物和疗法可以治疗这些疾病，但我们对情绪障碍中被破坏的生物过程的了解有限。然而，基因组技术的最新进展为这些疾病中存在的潜在基因改变和基因表达变化提供了新的见解。这些研究和其他研究已经确定了生长因子和/或生长因子信号、分子和过程的变化，这些信号、分子和过程已知会影响许多神经元功能(突触发生、神经发生)，这可能导致情绪障碍以及抗抑郁药物的作用。在过去的几年中，很明显，在发育中的和成人的大脑中存在着许多被称为microRNAs(MiRNAs)的小(~22nt)RNAs。MiRNAs通过降低靶mRNA水平和/或抑制翻译，作为基因表达的序列特异性转录后调节因子发挥作用。虽然最近才被发现，但miRNA基因可能占人类所有基因的1%以上，而且似乎所有基因中可能有20%是miRNA调控的靶标。然而，人们对成人大脑中miRNA的表达模式知之甚少，也不知道miRNA表达的变化是否发生在人类疾病中。最新数据(Schratt等人)已经表明miRNA功能、神经棘发育和一种特定的生长因子-脑源性神经营养因子(BDNF)的作用之间存在联系，这表明miRNA影响情绪障碍中改变的神经元功能。这项应用的目标是(1)使用深度测序技术确定和表征从单极患者和对照患者中获得的人死后大脑样本中的miRNA表达模式，以及(2)使用我们实验室开发的基于RNA探针的原位杂交方法来表征这些患者组中选定的miRNAs的空间模式。这些方法将使我们能够定义和量化这些大脑区域中已知的和新的microRNA含量，以及它们如何因疾病状态而变化。我们在确定受疾病调控的miRNA以及定义人类死后大脑中这种改变的miRNA调控的空间模式方面具有独特的地位，目的是更全面地了解这种miRNA在大脑和情绪障碍中的调控。与公共健康相关：我们的项目评估了被称为microRNAs(MiRNAs)的微小但新颖的遗传元素，这些基因元素被认为对细胞产生的蛋白质的类型或数量具有广泛影响。鉴于我们和其他人已经在成人脑组织中发现了这些miRNAs，这引发了关于这些遗传元件在大脑中的生物学作用以及miRNAs是否可能在脑部疾病(如精神疾病)中发挥作用的问题(S)。我们的应用程序试图确定这些miRNAs的水平是否因精神疾病状态而异，方法是使用从严重抑郁障碍和对照患者样本中分离的人死后脑组织中的新的深度测序方法来测量它们。

DESCRIPTION (provided by applicant): Mood disorders represent a class of devastating illnesses that have profound impact upon individuals, families, communities, employers, and health care systems. While many medications and therapies exist for the treatment of these illnesses, our understanding of the biological processes disrupted in mood disorders is limited. However, recent advances in genomic technologies have provided new insights into the underlying genetic alterations and gene expression changes present in these illnesses. These and other studies have identified alterations of growth factors and/or growth factor signaling, molecules and processes known to influence many neuronal functions (synaptogenesis, neurogenesis), that may contribute to mood disorders as well as the actions of antidepressants. During the past few years, it has become apparent that numerous small (~22nt) RNAs known as microRNAs (miRNAs) are present in the developing and adult brain. miRNAs function as sequence-specific post-transcriptional regulators of gene expression, by reducing target mRNA levels and/or inhibiting translation. Although only recently identified, miRNA genes are likely to represent more than 1% of all human genes, and it appears that perhaps 20% of all genes are targets of miRNA regulation. Yet, little is known about miRNA expression patterns in the adult brain, or whether changes in miRNA expression occur in human diseases. Recent data (Schratt et al.) has shown a link between miRNA function, neuronal spine development and the action of a specific growth factor, brain derived neurotrophic factor (BDNF), suggesting that miRNAs influence neuronal functions altered in mood disorders. The goals of this application are to (1) determine and characterize miRNA expression patterns in human postmortem brain samples obtained from unipolar and control patients using deep sequencing technologies and (2) characterized the spatial patterns of selected miRNAs in these same patient groups using RNA-probe based in situ hybridization methods developed in our laboratories. These approaches will permit us to define as well as quantify the known and novel microRNA content in these brain regions and how they vary by disease state. We are uniquely positioned to identify miRNAs that are regulated by disease as well as define the spatial patterns of this altered miRNA regulation in human postmortem brain with the intent to more fully understand this miRNA regulation in the brain and in mood disorders. PUBLIC HEALTH RELEVANCE: Our project evaluates small but novel genetic elements called microRNAs (miRNAs) that are thought to have broad influences on the types or amounts of proteins cells produce. Given that we and others have found these miRNAs in adult brain tissue, it prompts questions concerning the biological roles of these genetic elements in the brain and whether miRNAs might play a role(s) in diseases of the brain (e.g. psychiatric disease). Our application seeks to determine if the levels of these miRNAs vary by psychiatric disease state by measuring them using novel deep sequencing methods in human postmortem brain tissues isolated from major depressive disorder and control patient samples.