Role of microRNAs and RISC in activity regulated translation in neurons

microRNA 和 RISC 在神经元活性调节翻译中的作用

• 批准号: 8449921
• 负责人: GARY J BASSELL
• 金额: $ 23.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449921
• 关键词: Address; Affect; Agonist; Binding; Binding Proteins; Biochemical; Complex; Computer Simulation; Disease; Dopamine D1 Receptor; Drug Addiction; FMRP; Fragile X Mental Retardation Protein; Fragile X Syndrome; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genetic Translation; Glutamates; Goals; Lead; Learning; Luciferases; Mediating; Memory; Mental Retardation; Messenger RNA; Methods; MicroRNAs; Microarray Analysis; Microscopic; Modeling; Molecular; Mus; Neurodevelopmental Disorder; Neurologic; Neurons; Neurotransmitter Receptor; Neurotransmitters; Phosphorylation; Play; Positioning Attribute; Process; Protein Biosynthesis; Protein Dephosphorylation; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; RNA; RNA-Induced Silencing Complex; Receptor Activation; Receptor Signaling; Regulation; Reporter; Repression; Research; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Stimulus; Synapses; Synaptic plasticity; Testing; Therapeutic; Translational Repression; Translations; Untranslated RNA; Work; autism spectrum disorder; base; experience; mouse model; nervous system disorder; neuron development; neuropsychiatry; novel; overexpression; protein expression; public health relevance; response; spatiotemporal

DESCRIPTION (provided by applicant): A number of neurological and neuropsychiatric disorders, including fragile x syndrome, autism spectrum disorders, and drug addiction, may result from altered regulation of microRNAs. MicroRNAs (miRs) are small, conserved, noncoding RNAs that act in association with the RNA-induced silencing complex (RISC) to regulate gene expression post-transcriptionally. MicroRNAs are hypothesized to play a critical role in activity-regulated mRNA translation that controls neuronal development and synaptic plasticity. Our recent work has discovered a novel molecular mechanism for neurotransmitter-regulated protein synthesis that involves the release of a microRNA induced silencing complex (miRISC) from its target mRNA. This proposal will investigate whether this is used as a general mechanism for microRNAs to modulate activity mediated mRNA translation in neurons. We will identify new microRNAs and target mRNAs that utilize reversibility of the miRISC complex to regulate activity-mediated translation. A key question to be addressed is how different neurotransmitter signaling pathways may differentially affect microRNA/RISC targeting to mRNAs. Lastly, we will assess a role for phosphorylation of the fragile x mental retardation protein, FMRP, as a mechanism to regulate a subset of microRNAs at synapses. This research is expected to uncover new molecular mechanisms for activity mediated gene expression that allows for selective, dynamic and spatiotemporal control. The proposal will fill a critical gap in our understanding by characterization of a unifying molecular mechanism allowing for activity- regulated and sequence specific mRNA translation. Aim 1 will use candidate analysis and microarrays to test the hypothesis that neurotransmitter receptor signaling alters the interactions of microRNA/RISC complexes from target mRNAs as a novel mechanism for activity-regulated mRNA translation. Aim 2 will test the hypothesis that a subset of microRNAs and their regulated targeting to mRNAs by gp1 mGlu signaling is dysregulated in a mouse model of fragile x syndrome. This research has the potential to identify novel microRNAs regulated by neuronal activity, understand a unifying molecular mechanism for activity-regulated translation and help to elucidate the pathophysiology of a neurological disorder at the molecular level. This research is expected to have a broad impact on understanding how the posttranscriptional regulation of gene expression is dynamically controlled by RISC and miRNAs in response to neuronal activity to promote neuronal function, which may be altered in neurodevelopmental, neuropsychiatric disorders and drug addiction. These studies are envisioned to have important implications for future therapeutic strategies to manipulate activity-regulated protein synthesis in the treatment of neurological disorders and drug addiction.

描述（由申请人提供）：许多神经系统和神经精神疾病，包括脆弱的X综合征，自闭症谱系障碍和药物成瘾，可能是由于microRNA的调节改变而导致的。 microRNA（miR）是小的，保守的非编码RNA，与RNA诱导的沉默复合物（RISC）作用，以在转录后调节基因表达。假设microRNA在控制神经元发育和突触可塑性的活动调节的mRNA翻译中起关键作用。我们最近的工作发现了一种新型的神经递质调节蛋白质合成的分子机制，该机制涉及从其靶mRNA中释放MicroRNA诱导的沉默复合物（MIRISC）。该建议将调查这是否用作microRNA调节神经元中介导的mRNA翻译的一般机制。我们将确定新的microRNA和靶向miRNA，以利用Mirisc复合物的可逆性来调节活性介导的翻译。要解决的一个关键问题是，不同的神经递质信号通路如何差异化对mRNA的microRNA/RISC靶向。最后，我们将评估脆弱X智力低下蛋白FMRP磷酸化的作用，作为调节突触下microRNAS子集的一种机制。预计这项研究将揭示活性介导的基因表达的新分子机制，从而可以进行选择性，动态和时空对照。该提案将通过表征允许活性调节和序列特定的mRNA翻译的统一分子机制来填补我们的理解中的关键空白。 AIM 1将使用候选分析和微阵列来测试神经递质受体信号传导改变相互作用的假设 来自靶mRNA的microRNA/RISC复合物是活性调节的mRNA翻译的新机制。 AIM 2将检验以下假设：在脆弱X综合征的小鼠模型中，MicroRNA的子集及其通过GP1 MGLU信号传导对mRNA的靶向。这项研究具有鉴定由神经元活性调节的新型microRNA，了解一种用于活性调节翻译的统一分子机制，并有助于阐明分子水平上神经系统疾病的病理生理。预计这项研究将对理解基因表达的转录后调节如何受到RISC和miRNA对神经元活性的反应，以促进神经元功能，这可能会在神经发育，神经精神疾病和药物成瘾中改变。设想这些研究对未来的治疗策略具有重要意义，以在神经系统疾病和药物成瘾的治疗中操纵活动调节的蛋白质合成。