Stress Regulation of Non-Coding RNAs in Prefrontal Cortex

前额皮质非编码 RNA 的压力调节

基本信息

批准号：
8269664
负责人：
James P Herman
金额：
$ 19.53万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269664
关键词：
3&apos Untranslated Regions Affect Algorithms Alternative Splicing Amino Acid Sequence Animal Model Animals Behavioral Symptoms Binding Brain Brain region Brain-Derived Neurotrophic Factor Cells Chronic Chronic stress Complex Computing Methodologies Data Databases Development Disease Down-Regulation Emotional Disturbance Environmental Risk Factor Event Extinction (Psychology)Fright Functional RNA Functional disorder Future Gene Expression Gene Expression Regulation Gene Proteins Genes Genome Components Growth Factor Half-Life Human Hypersensitivity In Situ Hybridization Individual Intervention Life Life Stress Link Longevity Medial Mediating Mediator of activation protein Mental Depression Mental disorders Methods MicroRNAs Mining Modeling Modification Moods Morphology Mus Neurons Peptide Sequence Determination Physiological Play Poly A Post-Traumatic Stress Disorders Prefrontal Cortex Process Protein Biosynthesis Psychopathology RNA-Binding Proteins Rattus Recording of previous events Regimen Regulation Rodent Role Seeds Site Small RNA Stress Technology Tissues Translational Repression Untranslated Regions Variant Vertebral column Work base biological adaptation to stress cell type design follow-up gene repression infancy insight interest neurochemistry noradrenergic novel pre-clinical

项目摘要

DESCRIPTION (provided by applicant): The medial prefrontal cortex is a primary brain mediator of stress and mood. In humans and in animal models, medial prefrontal cortical dysfunction is associated with emotional disturbances, impaired fear extinction and inefficient termination of physiological stress responses. Medial prefrontal cortex dysfunction is linked to numerous mental illnesses, the most prominent being depression and post-traumatic stress disorder, diseases that are triggered by life stress and result in long-term inappropriate stress responding. Notably, gene expression in the prefrontal cortex is exquisitely sensitive to stress exposure, with the vast majority of regulated mRNAs showing pronounced down-regulation. Recent studies have convincingly demonstrated that non-coding RNAs, including microRNAs and alternatively expressed 3'-unstranslated (3'-UTR) mRNA sequences, play a major role in mRNA down-regulation in numerous tissues, including brain. This Exploratory Proposal is designed to perform detailed analysis of prefrontal cortical non-coding RNAs (microRNAs) and 3' UTRs (mRNAs) using newly-developed deep sequencing technology, affording a heretofore unprecedented assessment of miRNA and 3-UTR regulation by chronic unpredictable stress in rat. The unpredictable stress regimen reliably models physiological and behavioral symptoms of depression, allowing for extrapolation of preclinical findings to putative mechanisms of functional dysregulation in human cortex. Aim 1 will use deep sequencing methods to provide a comprehensive and quantitative analysis of existing as well as novel chronic stress-regulated miRNAs in the prefrontal cortex of C57BL6 mice. Aim 2 will apply the deep sequencing methods to identification of chronic stress-regulated 3'-UTR sequences. In both Aims, follow-up studies will verify specific regulation of targeted miRNAs and 3'-UTR sequences in the prefrontal cortex, and use anatomical methods to localize expression to distinct cortical subregions and cell types. Identification of novel stress-regulated miRNAs and 3'-UTRs in mouse will inform our understanding of mechanisms underlying human stress-related disease, and provide possible future targets for intervention in disease processes.

描述（由申请人提供）：内侧前额叶皮层是压力和情绪的主要大脑调节器。在人类和动物模型中，内侧前额皮质功能障碍与情绪障碍、恐惧消退受损和生理应激反应无效终止有关。内侧前额皮质功能障碍与许多精神疾病有关，其中最突出的是抑郁症和创伤后应激障碍，这些疾病是由生活压力引发并导致长期不适当的压力反应。值得注意的是，前额皮质中的基因表达对压力暴露极其敏感，绝大多数受调节的 mRNA 表现出明显的下调。最近的研究令人信服地证明，非编码 RNA，包括 microRNA 和替代表达的 3'-非翻译 (3'-UTR) mRNA 序列，在包括大脑在内的许多组织中的 mRNA 下调中发挥着重要作用。该探索性提案旨在利用新开发的深度测序技术对前额叶皮质非编码 RNA (microRNA) 和 3' UTR (mRNA) 进行详细分析，从而对慢性不可预测压力对 miRNA 和 3-UTR 的调节提供前所未有的评估在大鼠中。不可预测的应激疗法可靠地模拟了抑郁症的生理和行为症状，从而可以将临床前发现外推到人类皮质功能失调的推定机制。目标 1 将使用深度测序方法对 C57BL6 小鼠前额皮质中现有的以及新型的慢性应激调节 miRNA 进行全面的定量分析。目标 2 将应用深度测序方法来鉴定慢性应激调节的 3'-UTR 序列。在这两个目标中，后续研究将验证前额皮质中目标 miRNA 和 3'-UTR 序列的特异性调节，并使用解剖学方法将表达定位到不同的皮质亚区域和细胞类型。在小鼠中鉴定新型应激调节 miRNA 和 3'-UTR 将有助于我们了解人类应激相关疾病的机制，并为干预疾病过程提供可能的未来目标。