Controlling Spatially Restricted Intracellular Protein-Activity During Embryonic Neuronal Development Using Biomagnetic Nanotechnologies

使用生物磁纳米技术控制胚胎神经元发育过程中空间受限的细胞内蛋白质活性

• 批准号: 10319121
• 负责人: Maya Shelly
• 金额: $ 19.6万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319121
• 关键词: Address; Architecture; Axon; Biology; Brain; Cell membrane; Cell physiology; Cells; Chemicals; Complex; Cytoplasm; Cytoskeleton; Dendrites; Development; Developmental Process; Distant; Down-Regulation; Embryo; Embryonic Development; Engineering; Epilepsy; Event; Genetic; Goals; Hippocampus (Brain); Human; In Vitro; Instruction; Lead; Light; Magnetic nanoparticles; Magnetism; Metabolic; Methodology; Molecular; Molecular Genetics; Morphogenesis; Morphology; Motor; Mus; Nanotechnology; Neurites; Neurobiology; Neurons; Newborn Infant; Pathology; Phosphotransferases; Physiological; Polyhydramnios, megalencephaly, and symptomatic epilepsy; Preparation; Process; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Psyche structure; Regulation; Research Personnel; Rodent; Role; Route; STK11 gene; Signal Transduction; Slice; System; Technology; Therapeutic; Time; Tissues; Up-Regulation; autism spectrum disorder; base; bioelectronics; cell type; design; developmental neurobiology; disability; early childhood; fundamental research; genetic approach; hippocampal pyramidal neuron; innovation; insight; interdisciplinary approach; magnetic field; migration; mortality; mouse model; multidisciplinary; nanocomplexes; neuron development; neuropathology; neurotransmission; novel strategies; optogenetics; polarized cell; progenitor; protein activation; protein function; repaired; segregation; solid state electronics; spatiotemporal; uptake

Controlling spatially restricted intracellular protein-activity during embryonic neuronal development using biomagnetic nanotechnologies During mammalian embryonic development, neuronal cells polarize to create distinct cellular compartments of the axon and dendrite that inherently differ in the molecular composition of their cytoplasm, cytoskeleton, and plasma membrane. These differences underlie the unique morphology and function of these compartments and are responsible for directed information flow in the brain. Whereas axons transmit the chemical and electrical neuronal signals, the dendrites receive and integrate them. This polarized architecture arises from precisely regulated spatial segregation of specific intracellular proteins’ activities to discrete subcellular regions of a single neuronal cell that respectively dictate the axonal vs. dendritic fate. Aberrations in the localization of these proteins’ activity lead to defective neuron polarization and underlie severe human neurodevelopmental pathologies including intellectual and motor disabilities, epilepsy, and autism spectrum disorders. The ability to exert precise spatio-temporal control on intracellular protein-activity would permit directed regulation of neuronal polarization and may provide new approaches for the repair of the underlying neurodevelopmental pathologies. To date, no existing technologies, including leading molecular-genetics, light-controlled protein activation, or their combination using optogenetics, can allow sustained spatial restriction of intracellular protein-activity in the developing neuron. The main objective of this study is to address this fundamental challenge in neurobiology by developing biomagnetic-based nanotechnologies that will enable the spatial and temporal control of intracellular protein function in developing embryonic neurons. Specifically, we will develop biomagnetic-nanotechnologies to deliver and retain localized activity of the kinase LKB1, to dictate the process of axon formation in embryonic neurons in culture. Such a proposal demands a multi-disciplinary approach that integrates neurobiology, material engineering, and bioelectronics, for the development of protein based neuro-therapeutics. Many cellular events that dictate cell morphogenesis, metabolic state, or its unique physiological functions, in all cell types across evolutionarily distant species, are determined by highly localized and timed activity of specific intracellular proteins. The causative role of a critical intracellular protein in a particular cellular event or the ability to control that event can only be achieved by directed subcellular localization and retention of the protein or its activity. As current methodologies for spatio-temporal manipulation of protein function are inherently incapable of allowing the long-term spatial confinement of protein function, our studies will be applicable to many fundamental cellular events, as polarization and migration, and to the many intracellular proteins that control these cellular processes.

在胚胎神经元发育过程中控制空间受限的细胞内蛋白活性 生物磁性纳米技术 在哺乳动物胚胎发育期间，神经细胞极化以创建不同的细胞隔间 轴突和树突在其细胞质、细胞骨架和血浆的分子组成上固有的不同 薄膜。这些差异是这些隔室独特的形态和功能的基础，并 负责大脑中的定向信息流。而轴突传递化学和电神经元 信号，树突接收并整合它们。这种两极分化的体系结构源于精确调节的空间 将特定细胞内蛋白质的活性分离到单个神经元细胞的离散亚细胞区域， 分别决定轴突和树突的命运。这些蛋白质活性定位的异常导致 神经元极化缺陷，是严重的人类神经发育病理的基础，包括智力和 运动障碍、癫痫和自闭症谱系障碍。实施精确的时空控制的能力 细胞内蛋白活性将允许直接调节神经元极化，并可能提供新的 修复潜在神经发育病理的方法。到目前为止，还没有现有的技术， 包括领先的分子遗传学，光控制的蛋白质激活，或者利用光遗传学的它们的组合， 可以允许在发育中的神经元中持续的细胞内蛋白质活性的空间限制。主要目标 这项研究的目的是通过发展生物磁学来解决神经生物学中的这一根本挑战 纳米技术将使细胞内蛋白质功能的空间和时间控制在发展中 胚胎神经元。具体地说，我们将开发生物磁性纳米技术，以提供和保留本地化 激酶LKB1的活性，以决定培养的胚胎神经元中轴突的形成过程。这样的一个 提案需要一种多学科的方法，将神经生物学、材料工程和 生物电子学，用于发展基于蛋白质的神经疗法。许多细胞事件决定了细胞 形态发生，代谢状态，或其独特的生理功能，在所有类型的细胞中，跨越进化的遥远 物种，由特定细胞内蛋白的高度局部化和定时活性决定。A的致因作用 特定细胞事件中的关键细胞内蛋白或控制该事件的能力只能通过以下方式实现 蛋白质或其活性的定向亚细胞定位和保留。作为当前时空研究的方法论 蛋白质功能的操纵天生不能允许蛋白质的长期空间限制 功能，我们的研究将适用于许多基本的细胞事件，如极化和迁移，以及 许多控制这些细胞过程的细胞内蛋白质。