miRNA Control of Synaptic Stability and Structural Plasticity

突触稳定性和结构可塑性的 miRNA 控制

• 批准号: 10409879
• 负责人: Brandon Woods
• 金额: $ 1.5万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409879
• 关键词: Adult; Alzheimer' s Disease; Architecture; BRAIN initiative; Behavior Therapy; Behavioral; Biology; Brain; Calcium; Cellular Morphology; Disease; Drosophila genus; Ensure; Environment; Exercise; FMR1; Foundations; Genes; Genetic; Genetic Transcription; Goals; Individual; Lead; Learning; Mediating; MicroRNAs; Molecular; Molecular Analysis; Morphogenesis; Morphology; Nerve Degeneration; Nervous system structure; Neuromuscular Junction; Neuronal Plasticity; Neurons; Parkinson Disease; Pathogenesis; Pathway interactions; Phase; Phenotype; Physiological; Positioning Attribute; Post-Transcriptional Regulation; Research Project Grants; Shapes; Signal Transduction; Solid; Structure; Synapses; Synaptic plasticity; System; Thinking; Training; Translations; Work; fascinate; genetic analysis; genetic approach; interest; loss of function; neural circuit; neural model; neuronal circuitry; novel; optogenetics; programs; relating to nervous system; response; ribosome profiling; skills; sound; targeted treatment

PROJECT SUMMARY / ABSTRACT What fascinates me is the ability of the nervous system to mediate our adaptive responses to our changing environment and our changing behavioral states. As an entry point into this phenomenon, in my graduate training, I've used the Drosophila neuromuscular junction (NMJ) to build expertise in applying genetic and molecular analysis to understand how neural circuitry is adapted downstream of physiological input. In this context, at the cellular level, I've been most curious as to how neurons and their targets adapt highly specialized and complementary cellular morphologies during synaptic morphogenesis (SM). At the molecular level, neural activity initiates the deployment of calcium-dependent transcriptional and post- transcriptional programs that regulate synaptic morphology and organization. After learning about factors that control local translation within the synaptic compartment, such as the fragile X mental retardation protein (FMRP), I became very interested in post-transcriptional control of SM. Mechanistically, I am interested in how the translation of individual genes is controlled downstream of neural-activity during SM, which lead me to studying miRNAs. In my dissertation work thus far, I have identified several miRNAs as essential for activity- dependent morphogenesis of the NMJ terminal including miR-973. MiR-973 loss of function revealed a novel phenotype and suggested that it is required for activity-dependent synapse stability. Through these efforts, I have developed a sound understanding of approaches to characterize changes in synaptic architecture and plasticity. I will build upon this skill set in the F99 phase of this proposal by using optogenetics, ribosome profiling, and genetic approaches to resolve the mechanistic contribution of miR-973 in synaptic stability at the NMJ. Concurrently, I have developed a training plan with my sponsor and co- sponsor to ensure that I am actively thinking about the broader relevance of my work to synaptic plasticity in mammalian systems. Collectively, training during the F99 phase will provide a solid foundation that will enable me to construct effective experimental approaches to studying neural plasticity in a broad range of contexts. Moving forward, I will be in great position to transition into the K00 phase where I will apply my expertise in synaptic morphogenesis to exercise-mediated neural plasticity in the adult mammalian brain. My ultimate goal is to utilize this approach to identify novel molecular pathways and signaling factors that mediate neural plasticity as potential targets for therapeutic applications, which aligns with the Brain Initiative on Neurotherapeutics and Mechanisms shaping neuronal circuitry.

项目总结/摘要 让我着迷的是神经系统能够调节我们对环境的适应性反应， 不断变化的环境和我们不断变化的行为状态。作为进入这一现象的切入点， 在研究生培训中，我使用果蝇神经肌肉接头（NMJ）来建立应用 遗传和分子分析，以了解神经回路是如何适应下游的生理 输入.在这种情况下，在细胞水平上，我最好奇的是神经元和它们的目标如何适应 在突触形态发生（SM）过程中高度特化和互补的细胞形态。在 在分子水平上，神经活动启动钙依赖性转录和后 转录程序，调节突触形态和组织。在了解了 控制突触区室内的局部翻译，如脆性X智力低下蛋白 （FMRP），我对SM的转录后控制非常感兴趣。从机制上讲，我对 在SM期间，单个基因的翻译是如何在神经活动的下游被控制的，这使我 to studying研究miRNAs微RNA RNA.到目前为止，在我的论文工作中，我已经确定了几种对活性至关重要的miRNA- 包括miR-973在内的NMJ末端的依赖性形态发生。MiR-973功能丧失揭示了一种新的 表型，并建议它是所需的活动依赖性突触的稳定性。 通过这些努力，我对描述变化的方法有了很好的理解 在突触结构和可塑性方面。我将在本建议书的F99阶段使用 光遗传学、核糖体分析和遗传学方法来解决miR-973的机制贡献 突触稳定性的影响同时，我与我的赞助商和合作伙伴制定了一个培训计划。 赞助商，以确保我积极思考我的工作更广泛的相关性，以突触可塑性， 哺乳动物系统总的来说，F99阶段的培训将提供坚实的基础， 我构建有效的实验方法来研究神经可塑性在广泛的背景下。 展望未来，我将处于过渡到K 00阶段的有利位置，在那里我将运用我的专业知识， 成年哺乳动物大脑中运动介导的神经可塑性的突触形态发生。我的最终目标 是利用这种方法来确定新的分子途径和信号传导因子， 可塑性作为治疗应用的潜在目标，这与大脑倡议一致， 神经治疗学和神经回路形成机制。