The mechanical control of the embryonic development of the central nervous system

中枢神经系统胚胎发育的机械控制

• 批准号: 8928261
• 负责人: Kristian Franze
• 金额: $ 18.35万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928261
• 关键词: Affect; Animal Model; Area; Atomic Force Microscopy; Axon; Biochemical; Biological Models; Brain; Cells; Cellular Structures; Chemicals; Complex; Cues; Data; Defect; Destinations; Development; Distant; Embryo; Embryonic Development; Emotions; Environment; Extracellular Matrix; Extracellular Structure; Failure; Foundations; Genetic; Goals; Growth; Hereditary Disease; Human; Human Genetics; Image; In Vitro; Knowledge; Label; Laboratories; Lead; Learning; Life; Maps; Measurement; Measures; Mechanics; Memory; Mental disorders; Methods; Modification; Molecular; Morphogenesis; Morphology; Motion; Natural regeneration; Nerve Regeneration; Nervous system structure; Neuraxis; Neurodevelopmental Disorder; Neuroglia; Neurons; Pathway interactions; Pattern; Process; Property; Proteins; Research; Resolution; Rest; Retinal Ganglion Cells; Signal Transduction; Spinal cord injury; Staging; Structure; Techniques; Time; Tissues; Work; Xenopus; axon growth; axon guidance; axonal guidance; axonal pathfinding; base; body system; brain cell; brain tissue; developmental neurobiology; genetic manipulation; in vivo; interest; nervous system development; neuron development; neuronal cell body; neuronal growth; neuronal guidance; neurotransmission; preference; prevent; public health relevance; receptor; relating to nervous system; repaired; research study

 DESCRIPTION (provided by applicant): The nervous system, which is mainly built up by neurons and glial cells, is our most complex organ system. Neurons are the cells responsible for transmitting, processing, and storing information. During embryonic development, neurons extend long processes (axons) that follow well-defined, intricate pathways and make predictable connections to distant neurons or other target cells. Failure in connecting to the correct targets may result in severe defects. The number of known neurodevelopmental disorders related to aberrant axon connectivity in humans as a consequence of defective axon guidance is increasing rapidly. Almost everything we currently know about how axons are guided to their destination is based on biochemical signaling between neurons and their environment. Research on model organisms has provided tremendous advances in our understanding of the molecules (e.g., chemical guidance cues and their receptors) that govern axonal growth and guidance. However, axonal growth involves motion, and motion must involve forces. In spite of this, very little is known about the mechanical interactions of neurons with their environment. In the proposed project, we will, for the first time, investigate what mechanical signals axons encounter in the developing embryonic brain, how these signals change, and how they contribute to controlling axon growth. To achieve this goal, we will develop an experimental time-lapse technique, which is based on atomic force microscopy, to measure the dynamic mechanical properties of living Xenopus brain tissue, and simultaneously observe growing neuronal axons within the investigated area. Specific labeling of the neurons by the genetic insertion of a fluorescent protein will help distinguishing them from the rest of the tissue. This way, we will learn where and when in the brain stiffness gradients are found, how local tissue stiffness changes, and if neuronal axons show a preference for a certain range of tissue stiffness as suggested by preliminary experiments of our laboratory. Once we know the mechanical properties of the brain at each developmental stage, we will illuminate which cellular and extracellular structures are responsible for the measured properties. Finally, we will locally and globally interfere with tissue stiffness using pharmacological, genetic and physical approaches, and observe the effect of our treatment on axonal pathfinding. Thus, this project will illuminate a possible involvement of developmental tissue mechanics in neuronal growth and guidance. It has hence a great potential to lay the foundation for a new branch of developmental neurobiology, and it could ultimately greatly contribute to understanding and preventing and / or treating neurodevelopmental and also psychiatric disorders. Ultimately, knowledge gained in this project could also tremendously contribute to facilitate regeneration of damaged neurons after spinal cord injuries, which are currently incurable, and which have so far being investigated mostly from a biochemical point of view.

 神经系统主要由神经元和神经胶质细胞组成，是人类最复杂的器官系统。神经元是负责传输、处理和存储信息的细胞。在胚胎发育过程中，神经元延伸出长长的突起（轴突），这些突起遵循明确的、复杂的通路，并与远处的神经元或其他靶细胞建立可预测的连接。连接到正确目标的失败可能会导致严重的缺陷。由于轴突引导缺陷，与人类异常轴突连接相关的已知神经发育障碍的数量正在迅速增加。我们目前所知道的关于轴突如何被引导到其目的地的几乎所有信息都是基于神经元与其环境之间的生化信号。对模式生物的研究为我们对分子的理解提供了巨大的进步（例如，化学引导信号及其受体），其支配轴突生长和引导。然而，轴突生长涉及运动，而运动必须涉及力。尽管如此，人们对神经元与其环境的机械相互作用知之甚少。在拟议的项目中，我们将首次研究轴突在发育中的胚胎大脑中遇到的机械信号，这些信号如何变化，以及它们如何有助于控制轴突生长。为了实现这一目标，我们将开发一种实验性的时间推移技术，这是基于原子力显微镜，测量活爪蟾脑组织的动态力学性能，并同时观察正在生长的神经元轴突内的调查区域。通过基因插入荧光蛋白对神经元进行特异性标记，将有助于将它们与其他组织区分开来。通过这种方式，我们将了解在大脑中何时何地发现硬度梯度，局部组织硬度如何变化，以及神经元轴突是否表现出对我们实验室初步实验所建议的一定范围的组织硬度的偏好。一旦我们知道大脑在每个发育阶段的机械特性，我们将阐明哪些细胞和细胞外结构负责测量的特性。最后，我们将使用药理学，遗传学和物理方法局部和全局干扰组织硬度，并观察我们的治疗对轴突寻路的影响。因此，该项目将阐明发育组织力学在神经元生长和指导中的可能参与。因此，它有很大的潜力，奠定基础的一个新的分支发育神经生物学，它最终可能大大有助于理解和预防和/或治疗神经发育和精神疾病。最终，在这个项目中获得的知识也可以极大地促进脊髓损伤后受损神经元的再生，脊髓损伤目前是无法治愈的，迄今为止主要从生物化学的角度进行研究。