Molecular Mechanisms of Synapse Coordination

突触协调的分子机制

• 批准号: 10413160
• 负责人: Elizabeth Anne Martin
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413160
• 关键词: Adult; Animal Model; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biological Models; Biological Process; Biology; Brain; Cells; Cellular biology; Chemical Synapse; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Dendrites; Development; Dissection; Electrical Synapse; Embryo; Epilepsy; Equilibrium; Fellowship; Foundations; Genes; Genetic; Goals; Golgi Apparatus; Grant; Growth; Image; In Vitro; Institution; Investigation; Knowledge; Learning; Ligation; Light; Manuscripts; Mauthner' s neuron; Mediating; Membrane Proteins; Mentors; Molecular; Nervous system structure; Neurodevelopmental Disorder; Neurons; Neurotransmitters; Oregon; Organ; Pattern; Population; Positioning Attribute; Process; Proteins; Recycling; Regulation; Research; Research Methodology; Research Personnel; Role; Stereotyping; Synapses; Techniques; Tertiary Protein Structure; Therapeutic Intervention; Time; Training; Universities; Vertebrates; Writing; Zebrafish; autism spectrum disorder; collaborative environment; design; experience; gap junction channel; in vivo; innovation; insight; neural circuit; post-doctoral training; protein distribution; protein transport; rational design; statistics; supportive environment; synaptogenesis; trafficking

PROJECT SUMMARY / ABSTRACT The brain is an exquisitely complex organ. This complexity is not born out of its estimated 82 billion neurons, but instead in the trillions of specific connections these neurons make between one another during development called synapses. Yet, it is fundamentally unknown how the many different types of synapses form during development, nor is it known how synapse populations coordinate formation to create a working balance within in a neural circuit. This is a critical gap in the understanding of early brain development as numerous neurodevelopmental disorders, such as autism and epilepsy, are thought to arise from improper synapse formation resulting in circuit imbalances. Synapses are broadly defined into two groups: electrical synapses which form first and persist into adulthood; and chemical synapses which develop after electrical synapses and communicate via chemical neurotransmitters. While the biochemical makeup of electrical and chemical synapses are distinct, suggesting different processes regulate their formation, the autism- and epilepsy-associated gene Neurobeachin is required for both electrical and chemical synapse formation. The goal of this proposal is to 1) identify the molecular mechanisms used by Neurobeachin to regulate electrical and chemical synapse formation, and 2) determine if these mechanisms are similar to or distinct from one another. To realize this goal, the zebrafish Mauthner circuit will be used as it is ideal for dissection of Neurobeachin function during early development in vivo. Mauthner neurons make identifiable, stereotyped electrical and chemical synapses that are easily observed in developing embryos and accessible to cell biological, genetic, and biochemical investigation. Together, this proposal will unlock the shared mechanisms guiding electrical and chemical synapse formation and shed new light onto a molecule critical for brain development and implicated in various neurodevelopmental disorders ultimately leading to the design of rational therapeutic interventions. This proposal is designed to provide training in cutting edge CRISPR editing, dynamic live imaging, and sophisticated cell biology and biochemistry techniques within the zebrafish model system across early brain development at the University of Oregon. The University of Oregon is the birthplace of the zebrafish as a model organism and the preeminent institution to learn innovative zebrafish techniques among a highly collaborative and supportive environment of researchers. This experience will train the postdoctoral researcher in advanced research methodology and quantitative analysis, statistics, manuscript writing, and mentoring techniques necessary for successful growth into an independent academic research position.

项目总结/摘要 大脑是一个极其复杂的器官。这种复杂性并不是由其估计的820亿个神经元产生的， 而是这些神经元之间数以万亿计的特定连接， 称为突触。然而，从根本上说，我们还不知道许多不同类型的突触是如何形成的， 在发育过程中，也不知道突触群体如何协调形成，以创造一个工作的 神经回路中的平衡这是理解早期大脑发育的一个关键空白， 许多神经发育障碍，如自闭症和癫痫，被认为是由不适当的 突触形成导致电路不平衡。 突触大致分为两类：首先形成并持续到成年期的电突触; 以及在电突触之后发展的化学突触，它们通过化学物质进行交流。 神经传递素虽然电突触和化学突触的生化组成是不同的，这表明 不同的过程调节它们的形成，自闭症和癫痫相关基因Neurobeachin是 这是电突触和化学突触形成所必需的本提案的目标是：（1）确定 Neurobeachin用于调节电和化学突触形成的分子机制，以及2） 确定这些机制是否彼此相似或不同。为了实现这一目标，斑马鱼 将使用Mauthner电路，因为它是在早期发育期间解剖Neurobeachin功能的理想选择， vivo. Mauthner神经元制造可识别的、定型的电和化学突触， 在发育中的胚胎中观察到，并可用于细胞生物学，遗传学和生物化学研究。 总之，这项提议将解开指导电和化学突触形成的共同机制 并揭示了一种对大脑发育至关重要的分子， 神经发育障碍，最终导致设计合理的治疗干预措施。 该提案旨在提供尖端CRISPR编辑，动态实时成像， 在斑马鱼模型系统中的复杂细胞生物学和生物化学技术， 在俄勒冈州大学的发展。俄勒冈州大学是斑马鱼的发源地， 模式生物和卓越的机构，以学习创新的斑马鱼技术之间的高度 研究人员的协作和支持环境。这一经验将培养博士后研究人员 在先进的研究方法和定量分析，统计学，手稿写作和指导， 成功成长为独立的学术研究职位所必需的技术。