Investigating novel mechanisms that underlie glial-mediated synapse elimination in development and aging

研究发育和衰老过程中神经胶质介导的突触消除的新机制

• 批准号: 10721645
• 负责人: Taylor Reagan Jay
• 金额: $ 11.24万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721645
• 关键词: Address; Age-associated memory impairment; Aging; Biological; CD36 gene; Cell Culture Techniques; Data; Development; Developmental Process; Disease; Drosophila genus; Enzyme-Linked Immunosorbent Assay; Epilepsy; Event; Exhibits; Functional disorder; Gene Expression Profiling; Genes; Genetic Screening; Genetic Transcription; Goals; Immune system; Immunologic Receptors; Impairment; Label; Life; Ligands; Longevity; Maintenance; Mammals; Maps; Mediating; Mediator; Modeling; Molecular; Nerve Degeneration; Nervous System; Nervous System Physiology; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroglia; Neurons; Pathologic; Pathology; Pathway interactions; Play; Process; Proteins; Reagent; Regulation; Reporter; Research; Research Personnel; Role; Schizophrenia; Signal Pathway; Specific qualifier value; Specificity; Synapses; System; Technical Expertise; Validation; Visualization; Work; age related; age related neurodegeneration; autism spectrum disorder; brain health; candidate identification; cell type; differential expression; experimental study; insight; knock-down; mouse model; nervous system development; novel; postsynaptic; presynaptic; receptor; screening; synaptogenesis; tool; trafficking

Project Summary Formation and maintenance of synaptic connections between appropriate neuronal partners is essential for proper nervous system function. Indeed, impairments in either initial synapse formation or in subsequent developmental synapse elimination underlie many neurodevelopmental disorders. Synapse elimination that occurs outside of appropriate developmental contexts underlies synaptic loss associated with age-related cognitive decline and in neurodegenerative diseases. Thus, defining the mechanisms that underlie the regulation of synapse number will provide insight into how appropriate connections are formed during development, and these pathologies of synapse elimination. Despite its essential role in nervous system development and function throughout life, we still know little about the mechanisms underlying this process. We do know, however, that glia are required. In order to identify novel glial regulators of synapse development, I completed a forward genetic screen in Drosophila, and identified 91 molecules that, when knocked down in glia, alter synapse number. Among these molecules is the immune receptor Crq, which I found is required for glial elimination of synapses in development. This proposal will focus on understanding Crq’s role in synapse elimination, in order to gain insight into the larger questions of which synapses undergo developmental synapse elimination, the mechanisms underlying the specificity of this process, and whether these same mechanisms are re-used in pathological synapse loss associated with aging. Aim 1 will address the question of which synapses undergo developmental elimination across the nervous system and evaluate which of these are Crq-dependent. I have recently developed an inducible pre-synaptic label that makes this work possible, and will generate inducible postsynaptic labels as part of this aim. Aim 2 will use proximity labeling to identify the neuronal ligand(s) for Crq that act to specify which synapses undergo elimination, and will identify how expression and localization of these ligands are regulated. Aim 3 will define which synapses are lost with aging, and identify whether Crq acts as a common mediator of synaptic loss in development and aging. I will also perform a targeted screen based on a recent transcriptional profiling experiment I completed to identify additional glial regulators of age-related synaptic loss. Together, these studies will address the mechanisms by which synapses are targeted for elimination and how. This is a key question in achieving the larger goal of understanding how neurons and glia work together to create and maintain appropriate synaptic connections throughout life. Dissecting these mechanisms will also provide insight into the process of age-related synaptic loss that underlies age-related cognitive decline. In addition, performing this work will allow me to address existing gaps in my technical skills that will allow me to carry out my long-term research goals as an independent invesitigator.

项目摘要 适当的神经元伴侣之间的突触连接的形成和维护对于 适当的神经系统功能。实际上，初始突触形成或随后的损害 发展突触消除是许多神经发育障碍的基础。突触消除了这一点 发生在适当的发育环境之外，是与年龄有关的合成损失的基础 认知能力下降和神经退行性疾病。这是定义监管基础的机制 突触号码将提供有关开发过程中如何形成适当联系的洞察力，以及 这些消除突触的病理。 尽管它在神经系统的发展和一生中的功能中至关重要，但我们仍然对 该过程的基础机制。但是，我们确实知道需要神经胶质。为了识别新颖 我在突触发展的神经胶质调节剂中完成了果蝇的正向遗传筛查，并确定了91 分子在胶质细胞中撞倒时会改变突触数。在这些分子中是免疫 我发现的受体CRQ是消除发育中的突触所必需的。该建议将集中 了解CRQ在淘汰突触中的作用，以深入了解更大的问题 突触欠发达突触消除，其特异性的基础机制 过程，以及这些相同的机制是否在与衰老相关的病理突触丧失中重复使用。 AIM 1将解决哪些突触经历紧张的发育消除的问题 系统并评估其中哪种是CRQ依赖性的。我最近开发了诱导的突触前 这项工作成为可能的标签，并将产生诱导的突触后标签作为此目标的一部分。 AIM 2意志 使用接近标记来识别CRQ的神经元配体，以指定突触经历哪些突触 消除，并将确定如何调节这些配体的表达和定位。 AIM 3将定义 随着衰老而丢失哪些突触，并确定CRQ是否充当突触损失的常见介体 发展和衰老。我还将根据最近的转录分析执行目标屏幕 实验I完成了，以确定与年龄相关的合成损失的其他神经胶质调节剂。 总之，这些研究将解决突触的针对消除以及如何定位的机制。 这是实现了解神经元和神经胶质如何共同工作的更大目标的关键问题 在整个生命中创建并保持适当的突触连接。解剖这些机制也将 提供有关与年龄相关的合成损失过程的见解，该过程是与年龄相关的认知下降构成的。 此外，执行这项工作将使我能够解决我的技术技能的现有差距，这将使我能够 作为独立研究者，我的长期研究目标。