Regulation of Retinal Physiology by micro-RNAs

micro-RNA 对视网膜生理学的调节

基本信息

批准号：
8627170
负责人：
Krzysztof Palczewski
金额：
$ 34.95万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627170
关键词：
Adult Algorithms Anatomy Animals Base Pairing Biochemical Bioinformatics Cell Death Cells Cessation of life Data Degenerative Disorder Development Disease Disease model Event Exhibits Exposure to Eye Gene Cluster Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Health Immunoprecipitation Investigation Knockout Mice Light Link Measures Mediating Messenger RNA MicroRNAs Mitotic Molecular Mus Open Reading Frames Organ Pathology Pathway interactions Phenotype Photoreceptors Physiological Physiological Processes Physiology Plants Play Porifera Protein Biosynthesis Proteins RNA RNA Binding RNA-Binding Proteins RNA-Induced Silencing Complex Regulation Repression Residual state Retina Retinal Retinal Degeneration Retinitis Pigmentosa Role Seeds Sensory Site Stress Techniques Technology Tissues Translational Repression Translations Visual system structure base crosslink in vivo insight interest loss of function mouse model new technology next generation sequencing novel novel strategies paralogous gene prevent public health relevance research study treatment strategy vision development

项目摘要

DESCRIPTION (provided by applicant): Micro-RNAs (miRNAs) are small, stable RNA molecules that post-transcriptionally regulate gene expression in plants and animals. They act by base pairing to partially complementary sequences on target messenger RNAs to inhibit protein synthesis, primarily through translational repression and mRNA destabilization. More than 250 miRNAs are reportedly expressed in the retina, and miRNA gene regulation has been shown to impact retinal development, function, and disease. miRs -96, -183, and -182 comprise an evolutionarily conserved, paralogous gene cluster. Simultaneous partial disruption of the activities of these miRNAs in photoreceptors results in a robust light-induced retinal degeneration phenotype, implying that these miRNAs serve a neuroprotective function during exposure to light. Thus, this miRNA-mediated photoreceptor survival pathway is a novel target for potential therapy of retinal degenerative disorders. To evaluate the impact of the miR-183 cluster on photoreceptor survival more directly in the context of retinal degenerative disease, the consequences of miR-183 cluster loss-of-function will be evaluated in new mouse models of autosomal dominant and autosomal recessive retinitis pigmentosa. A knockout mouse model will be generated to determine the impact of complete loss of miRNA cluster activity. Additionally, a combination of 'top-down' and 'bottom-up' approaches will be employed to dissect out the molecular events underlying miRNA-mediated photoreceptor protection. Newly developed biochemical techniques will be used to identify functionally relevant direct targets of these miRNAs in the retina, and next generation sequencing technology will be employed to evaluate miRNA cluster-dependent alterations in gene expression that occur after exposure to intense light. Results of these investigations will provide insights into gene regulation networks involved in protecting photoreceptors against stress-induced death. These experiments promise to yield novel approaches to treat or prevent blinding diseases.

描述（由申请人提供）：微RNA（miRNA）是小的，稳定的RNA分子，在转录后调节植物和动物中的基因表达。它们通过基础配对与目标信使RNA的部分互补序列起作用，主要通过翻译抑制和mRNA不稳定抑制蛋白质的合成。据报道，在视网膜中表达了250多个miRNA，并且已显示miRNA基因调节会影响视网膜发育，功能和疾病。 miRS -96，-183和-182包括进化保守的寄生虫基因簇。这些miRNA在光感受器中的活性的部分破坏会导致光诱导的视网膜变性表型，这意味着这些miRNA在暴露于光期间起着神经保护功能。因此，这种miRNA介导的感光体存活途径是视网膜退行性疾病潜在治疗的新靶标。在视网膜退行性疾病的背景下，更直接地评估miR-183簇对光感受器存活的影响， MiR-183功能障碍的后果将在新的常染色体显性和常染色体隐性视网膜炎的新小鼠模型中评估。将生成敲除小鼠模型，以确定miRNA簇活性的完全丢失的影响。此外，将采用“自上而下”和“自下而上”方法的组合来剖定miRNA介导的光感受器保护的基础分子事件。新开发的生化技术将用于识别视网膜中这些miRNA的功能相关的直接靶标，并将采用下一代测序技术来评估暴露于强光后发生的基因表达中miRNA簇依赖性的变化。这些研究的结果将提供有关保护感光者免受压力引起的死亡的涉及的基因调节网络的见解。这些实验有望产生新颖的方法来治疗或预防盲目疾病。