miRNA Gene Regulatory Networks and their Role in Diseases of the Nervous System

描述（由申请人提供）：摘要：小RNA介导的基因表达调控是一个新的除了基本的基因调控机制，有助于协调可能的真核基因组的每个基因的时间和空间基因表达。体细胞组织中小RNA的主要来源是编码进化保守序列的短dsRNA发夹的miRNA基因。神经系统疾病，如精神分裂症，抑郁症，双相情感障碍或自闭症在分子水平上知之甚少，但推测是由神经元回路的基因调控网络的扰动引起的。在本申请中，我们建议探索miRNA调控网络是否在这些和其他神经系统疾病中发挥作用。这将通过三个实验室的高度合作和互动努力来实现，这些实验室将开发识别小RNA及其调控靶点的方法，并使用生物化学，细胞和动物模型系统来研究基因调控的详细分子机制。本研究的具体目的是：1.定义正常和疾病状态的解剖学和/或功能不同的大脑区域的小RNA含量。在分析模型中包括神经元和神经系统细胞系以及神经元干细胞祖细胞和衍生细胞或结构。2.定义小鼠、食蟹猴和人脑（正常和疾病状态）中最丰富和特异性表达的miRNA的空间和细胞类型特异性表达。3.使用基因组学和生物化学方法确定小鼠脑和正常及患者脑区域中miRNA的靶点。4.确定miRNAs在小鼠胚胎干细胞神经元分化中的作用。Lay声明：虽然努力确定负责抑郁症，双相情感障碍，自闭症和精神分裂症的基因在过去一直具有挑战性，本研究的目的将是提供一个新的一类小的非编码基因（microRNA）的表达图谱从正常和精神残疾的主题，以确定一个子集的高度表达的microRNA在中枢神经系统中的作用。了解microRNA的特定相互作用及其靶向和调节的基因网络可能最终有助于我们理解和治疗这些使人衰弱的精神疾病。

DESCRIPTION (provided by applicant): Abstract: Small RNA mediated regulation of gene expression is a recent addition to fundamental gene regulatory mechanisms that contribute to coordinate temporal and spatial gene expression of possibly every gene of a eukaryotic genome. The predominant sources of small RNA in somatic tissues are miRNA genes that encode short dsRNA hairpins of evolutionary conserved sequences. Disorders of the nervous system, such as schizophrenia, depression, bipolar disorder or autism are poorly understood at a molecular level but presumed to be caused by perturbation in gene regulatory networks of neuronal circuits. In this application we propose to explore if miRNA regulatory networks play a role in these and other diseases of the nervous system. This will be achieved through a highly collaborative and interactive effort of three laboratories that will develop methods for identification of small RNAs and their regulated targets and use biochemical, cell and animal model systems to study the detailed molecular mechanisms of gene regulation. The specific aims of this study are: 1. Define the small RNA content of anatomical and/or functionally distinct brain regions of normal and disease state. Include in the analysis model neuronal and nervous system cell lines as well as neuronal stem cell progenitors and derived cells or structures. 2. Define the spatial and cell type specific expression of the most abundantly and specifically expressed miRNAs in the brain of mouse, Macaca fascicularis, and human brain (normal and disease states). 3. Define the targets of miRNAs in mouse brain and normal and patient brain regions using genomic and biochemical approaches. 4. Determine the role of miRNAs in neuronal differentiation of mouse embryonic stem cells. Lay statement: Although efforts to identify genes responsible for major depression, bipolar disorder, autism, and schizophrenia have been challenging in the past, the purpose of this study will be to provide an expression atlas of a new class of small non-coding genes (microRNAs) from normal and mentally disabled subjects to determine the role of a subset of the highly expressed microRNAs in the central nervous system. Understanding the specific interactions of microRNAs and the network of genes they target and regulate may ultimately contribute to our understanding and treatment of these debilitating mental illnesses.