Fascin in brain development and function

肌成束蛋白在大脑发育和功能中的作用

• 批准号: 10676626
• 负责人: James Q Zheng
• 金额: $ 22.62万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676626
• 关键词: Actins; Adult; Axon; Biological Assay; Brain; Brain Diseases; Bundling; CRISPR/Cas technology; Cell Culture Techniques; Cells; Cellular Structures; Cellular biology; Complex; Cues; Cytoskeleton; Dendrites; Development; Disease; Electrophysiology (science); Embryonic Development; Employment; Environment; Epilepsy; Event; Exhibits; F-Actin; Family; Filopodia; Fingers; Genes; Growth Cones; Hippocampus; Image; Injections; Interneurons; Knock-out; Knowledge; Label; Maintenance; Membrane; Microfilaments; Molecular; Morphology; Mus; Neoplasm Metastasis; Nervous System; Neurons; Organelles; Pathologic; Physiological; Play; Property; Protein Isoforms; Proteins; Public Health; Regulation; Research; Role; Side; Signal Transduction; Structure; Synapses; Synaptic Transmission; Testing; Therapeutic Intervention; Thin Filament; Thinness; Time; Vertebral column; Viral; Work; Writing; axon growth; axon guidance; axonal pathfinding; axonal sprouting; brain tissue; cancer cell; cell motility; crosslink; dentate gyrus; extracellular; fascin; granule cell; hippocampal pyramidal neuron; in vivo; insight; migration; molecular targeted therapies; mossy fiber; nerve injury; neural circuit; neurodevelopment; neuron development; neurotransmission; response; scaffold; spatiotemporal; superresolution imaging; synaptogenesis

Project Summary The actin cytoskeleton and its dynamic regulation play an essential role in neuronal development and function. The proposed study aims to investigate the role of Fascin, a family of actin bundling proteins, in brain development and function. Fascin1 exhibits an intriguing expression profile in mammalian brains: it is highly expressed during development but the expression is substantially decreased in the adult brain During development, elongating axons are guided to their specific targets for synaptic connections. Axon pathfinding depends on the motile growth cone at the tip of developing axons, which senses and responds to a variety of extracellular signals to navigate through a complex and changing environment. The first part of the proposed study aims to test the hypothesis that fascin, a family of actin filament bundling proteins, functions in the formation and dynamic regulation of growth cone filopodia during axon guidance. The part of research will take advantage of our expertise in growth cone research, and employment of a multifaceted approach involving imaging, molecular manipulation, and combined assays in cell cultures and ex vivo brain tissues. While fascin1 expression is substantially reduced in adult brains, fascin1 remains highly expressed in adult hippocampus. We will test the exciting hypothesis that fascin1 plays an important role in the formation, maintenance, and remodeling of mossy fiber- CA3 synaptic connections. Using a combination of an in vivo labeling and manipulation, imaging, and electrophysiology, we aim to evaluate and establish, for the first time, the role of fascin1 and its actin bundling in brain development and synaptic regulation in adult brain. Given that elevated fascin1 levels have been associated with cancer cell metastasis, the proposed work on fascin1 will not only provide significant insights into the molecular mechanisms of brain development and function, but also extend our knowledge concerning the actin mechanisms underlying directed cell movement in many physiological and pathological events.

项目摘要 肌动蛋白细胞骨架及其动态调节在 神经元的发育和功能。拟议的研究旨在调查 Fascin是肌动蛋白捆绑蛋白的家族，在大脑发育和功能方面。 fascin1 在哺乳动物的大脑中表现出有趣的表达曲线：它是高度表达的 在开发过程中，但成人大脑的表达大大降低 在开发过程中，伸长轴突被带到其突触的特定靶标 连接。轴突探路取决于在 开发轴突，感应并响应各种细胞外信号 浏览复杂而不断变化的环境。提议的第一部分 研究旨在检验以下假设：肌动蛋白丝束蛋白的家族， 轴突期间生长锥丝状的形成和动态调节的功能 指导。研究的一部分将利用我们在增长锥方面的专业知识 研究和使用涉及成像的多面方法，分子 操作，并在细胞培养物和离体脑组织中进行合并测定。 虽然FASTIN1表达在成年大脑中大大降低，但Fascin1仍然存在 在成年海马中高度表达。我们将测试Fastin1的令人兴奋的假设 在苔藓纤维的形成，维护和重塑中起重要作用 CA3突触连接。结合体内标记和操纵的组合， 成像和电生理学，我们旨在首次评估和建立 fascin1及其肌动蛋白在大脑发育和突触调节中的作用 成人大脑。鉴于升高的fascin1水平与癌细胞有关 转移，拟议的关于fascin1的拟议工作将不仅提供重大见解 大脑发育和功能的分子机制，但也扩展了我们的 关于许多在许多人中的定向细胞运动的肌动蛋白机制的知识 生理和病理事件。