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产生深远影响的破坏性疾病。虽然存在许多治疗这些疾病的药物和疗法，但我们对情绪障碍中被破坏的生物过程的理解是有限的。然而，基因组技术的最新进展为这些疾病中存在的潜在遗传改变和基因表达变化提供了新的见解。这些和其他研究已经确定了生长因子和/或生长因子信号传导、已知影响许多神经元功能（突触发生、神经发生）的分子和过程的改变，这可能有助于情绪障碍以及抗抑郁药的作用。在过去的几年中，已经很明显，许多小的（~ 22 nt）RNA被称为microRNA（miRNA）存在于发育和成人大脑中。miRNA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。虽然最近才发现，但miRNA基因可能占所有人类基因的1%以上，并且似乎所有基因中可能有20%是miRNA调控的靶基因。然而，人们对成年人大脑中的miRNA表达模式知之甚少，或者miRNA表达的变化是否发生在人类疾病中。最新数据（Schratt等人）已经显示了miRNA功能、神经元棘发育和特异性生长因子脑源性神经营养因子（BDNF）的作用之间的联系，表明miRNA影响情绪障碍中改变的神经元功能。本申请的目的是（1）使用深度测序技术确定和表征从单极和对照患者获得的人类死后脑样品中的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表征这些相同患者组中选定miRNA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和新的microRNA含量，以及它们如何随疾病状态而变化。我们处于独特的位置，以确定由疾病调节的miRNA，以及定义这种改变的miRNA调节在人类死后大脑中的空间模式，目的是更全面地了解这种miRNA在大脑和情绪障碍中的调节。公共卫生相关性：我们的项目评估了被称为microRNAs（miRNAs）的小但新颖的遗传元件，这些元件被认为对细胞产生的蛋白质的类型或数量具有广泛的影响。鉴于我们和其他人已经在成人脑组织中发现了这些miRNAs，它引发了关于这些遗传元件在大脑中的生物学作用以及miRNAs是否可能在大脑疾病（例如精神疾病）中发挥作用的问题。我们的申请旨在确定这些miRNAs的水平是否因精神疾病状态而异，方法是使用新型深度测序方法在从重度抑郁症和对照患者样本中分离的人类死后脑组织中测量它们。

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.