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细胞内 神经元的发育和功能。本研究旨在探讨 成束蛋白，一个肌动蛋白捆绑蛋白家族，在脑发育和功能中的作用。Fascin1 在哺乳动物大脑中表现出一种有趣的表达模式： 但在成人脑中表达显著降低 在发育过程中，伸长的轴突被引导到它们特定的目标， 连接.轴突的寻路依赖于轴突顶端能动的生长锥， 正在发育的轴突，它能感知并响应各种细胞外信号， 在复杂多变的环境中游刃有余第一部分建议 这项研究的目的是检验一种假说，即肌成束蛋白，一种肌动蛋白丝束蛋白家族， 在轴突生长期生长锥丝状伪足的形成和动态调节中的作用 指导研究部分将利用我们在生长锥方面的专业知识 研究和采用多方面的方法，包括成像、分子 操作，以及在细胞培养物和离体脑组织中的组合测定。 虽然fascin 1在成人大脑中的表达大幅减少，但fascin 1仍然存在 在成年海马中高度表达。我们将测试一个令人兴奋的假设， 在苔藓纤维的形成、维持和重塑中起着重要作用， CA3突触连接。使用体内标记和操作的组合， 成像和电生理学，我们的目标是评估和建立，首次， fascin1及其肌动蛋白束在脑发育和突触调节中的作用 成人大脑鉴于fascin1水平升高与癌细胞 转移，对fascin1的拟议工作不仅将提供重要的见解， 大脑发育和功能的分子机制，而且还扩展了我们的 关于许多细胞定向运动的肌动蛋白机制的知识， 生理和病理事件。