Regulation of Retinal Physiology by micro-RNAs

micro-RNA 对视网膜生理学的调节

• 批准号: 8431587
• 负责人: Krzysztof Palczewski
• 金额: $ 35.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 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/8431587
• 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

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）：微小RNA（miRNA）是小的、稳定的RNA分子，在植物和动物中转录后调节基因表达。它们通过与靶信使RNA上的部分互补序列进行碱基配对来抑制蛋白质合成，主要通过翻译抑制和mRNA去稳定化。据报道，超过250种miRNA在视网膜中表达，并且miRNA基因调控已显示影响视网膜发育、功能和疾病。miR-96、-183和-182包含进化上保守的旁系同源基因簇。光感受器中这些miRNAs活性的同时部分破坏导致稳健的光诱导视网膜变性表型，这意味着这些miRNAs在暴露于光期间起到神经保护功能。因此，这种miRNA介导的感光细胞存活途径是视网膜退行性疾病潜在治疗的新靶点。为了更直接地评估miR-183簇在视网膜变性疾病背景下对光感受器存活的影响， 将在常染色体显性和常染色体隐性视网膜色素变性的新小鼠模型中评估miR-183簇功能丧失的后果。将产生敲除小鼠模型以确定miRNA簇活性完全丧失的影响。此外，将采用“自上而下”和“自下而上”方法的组合来剖析miRNA介导的感光细胞保护的分子事件。新开发的生化技术将用于识别视网膜中这些miRNA的功能相关直接靶点，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的miRNA簇依赖性改变。这些研究的结果将提供深入了解基因调控网络参与保护光感受器免受压力诱导的死亡。这些实验有望产生治疗或预防致盲疾病的新方法。