Control of miRNA-mediated translational repression in neurons

控制神经元中 miRNA 介导的翻译抑制

• 批准号: 8030383
• 负责人: Richard W. CARTHEW
• 金额: $ 17.89万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-10 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030383
• 关键词: 3' Untranslated Regions; Afferent Neurons; Behavioral; Binding; Binding Sites; Biochemical; Biological Assay; Brain; Cells; Complex; Coupled; Cytosol; Dendrites; Dendritic Spines; Development; Disease; Drosophila genus; Early Endosome; Endocytosis; Endosomes; Enzymes; Functional RNA; Functional disorder; Gene Expression; Genetic; Genetic Translation; Goals; Grant; Health; Lead; Link; Mediating; Membrane; Mental disorders; Messenger RNA; MicroRNAs; Modeling; Modification; Molecular; Nervous system structure; Neuromuscular Junction; Neurons; Nucleotides; Photoreceptors; Physiological; Protein Biosynthesis; Proteins; RNA; RNA, Messenger, Stored; Recruitment Activity; Regulation; Regulator Genes; Repression; Sorting - Cell Movement; Staging; Synapses; Synaptic plasticity; Technology; Testing; Transcript; Translational Repression; Translations; Vesicle; Work; cognitive enhancement; insight; interest; late endosome; nervous system disorder; novel therapeutics; parallel processing; receptor; research study; trafficking

DESCRIPTION (provided by applicant): Synaptic plasticity has been linked to the regulation of dendritic synthesis of proteins, whereby synaptic stimulation activates local translation of pre-existing mRNAs that are stored close to the synapse. Local protein synthesis at synapses can lead to long-lasting modification in synaptic strength and efficacy. A key unanswered question is how localized translation control occurs. Two features of control are apparent; there is long-term and constitutive silencing of translation but there is also rapid and inducible de-silencing of translation. This grant seeks to explore the mechanisms behind silencing/de-silencing. We are working with the assumption that some of this control is mediated by microRNAs. This remarkable class of non-coding RNAs repress the translation of mRNA transcripts, which contain miRNA-binding sites in their 3' untranslated regions. MicroRNAs located in dendrites are known to repress functionally important mRNAs, and derepress under certain conditions. Our goal is to understand how miRNAs lock up their target mRNAs, and how synaptic activities release their target mRNAs for translation. To this end, we have discovered that cells release targets when endocytosis occurs. Endosomes recruit repressed complexes to their limiting membranes, and as endosomes mature to late endosome stages, complexes are dissociated and turned over. This enables targets to be released. The aims of the grant are to determine if activity-dependent endocytosis releases mRNAs from miRNA-mediated repression in a non-synaptic and synaptic neuronal model. If we uncover such a mechanism, it would advance understanding of synaptic plasticity. The significance to health is manifold. Understanding the molecular mechanisms that regulate synaptic plasticity is of paramount importance to decipher behavioral plasticity, how mental illness can disrupt it, and guide development of new therapeutic technologies. PUBLIC HEALTH RELEVANCE: MicroRNAs are regulators of gene expression, and their dysfunction is linked to diverse forms of neurological disorders. This project is to understand how microRNAs control protein translation in neurons, particularly in synapses. Their relationship to synaptic plasticity is of particular interest.

描述（由申请人提供）：突触可塑性与蛋白质树突合成的调节有关，由此突触刺激激活存储在突触附近的预先存在的 mRNA 的局部翻译。突触的局部蛋白质合成可以导致突触强度和功效的持久改变。一个尚未解答的关键问题是本地化翻译控制是如何发生的。控制的两个特征是显而易见的：存在着长期的、本质性的翻译沉默，但也存在着快速的、可诱导的翻译去沉默。这笔赠款旨在探索沉默/去沉默背后的机制。我们假设部分控制是由 microRNA 介导的。这一类非凡的非编码 RNA 抑制 mRNA 转录物的翻译，这些转录物在其 3' 非翻译区含有 miRNA 结合位点。已知位于树突中的 MicroRNA 会抑制功能上重要的 mRNA，并在某些条件下解除抑制。我们的目标是了解 miRNA 如何锁定其目标 mRNA，以及突触活动如何释放其目标 mRNA 进行翻译。为此，我们发现细胞在发生内吞作用时释放靶标。内体将抑制的复合物募集到其限制膜上，并且当内体成熟到内体后期时，复合物被解离并翻转。这使得目标能够被释放。该资助的目的是确定在非突触和突触神经元模型中，活性依赖性内吞作用是否会从 miRNA 介导的抑制中释放 mRNA。如果我们发现这样的机制，它将促进对突触可塑性的理解。对健康的意义是多方面的。了解调节突触可塑性的分子机制对于破译行为可塑性、精神疾病如何破坏它以及指导新治疗技术的开发至关重要。 公共健康相关性：MicroRNA 是基因表达的调节因子，其功能障碍与多种形式的神经系统疾病有关。该项目旨在了解 microRNA 如何控制神经元（尤其是突触）中的蛋白质翻译。它们与突触可塑性的关系特别令人感兴趣。