Biomechanical Regulation in Human Neural Induction

人类神经感应的生物力学调节

• 批准号: 1662835
• 负责人: Yubing Sun
• 金额: $ 40万
• 依托单位: University of Massachusetts Amherst
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1662835&HistoricalAwards=false
• 关键词: Biomechanical; Regulation; Human; Neural; Induction; Biomechanical; Regulation; Human; Neural; Induction

Neural tube defects are among the most common birth defects and affect more than 500,000 infants worldwide each year. Neural tube defects can result in severe health problems, including paralysis of legs, brain damage, and even death. To develop novel approaches for the prevention and diagnosis of neural tube defects, a fundamental understanding of the development of the central nervous system is required. Using animal models, genetic and biochemical factors that regulate neural induction, the first stage of the central nervous system development, have been partially unraveled. Recent studies suggest that the cell fate decision in the neural induction is regulated by biomechanical cues. This mechanical mechanism is poorly understood and very difficult to study using animal models. This research will build a series of novel cell culture tools to investigate the genetic, biochemical and biomechanical interactions during neural induction. These new tools will provide the ability to perform experiments with lower costs and not using animal subjects to determine the mechanical effects on neural tube formation. Fundamental data on how the mechanical environment of the cells changes their behavior during neural tube development will be collected. The principal investigator will engage K-12, undergraduate and graduate students with diverse ethnic backgrounds and genders with this interdisciplinary bioengineering research, and encourage them to pursue science and engineering careers.This project will test the hypothesis that mechanical interactions dictate morphogenic events in neural development. Micropatterned cell culture environments are known to cause human cells to mimic the spatial patterning of neuroepithelial cells and neural plate border cells of the neural plate, and thus will be used to model neural induction. Drug treatment and a novel device which locally expands the cells located in the designated regions of micropatterns to dynamically regulate cell shape and force will be used to investigate how cell spatial patterning in the in vitro neural induction model regulates cell shape and force. The mechanotransduction pathways in neural induction will be investigated, focusing on the functional involvement of YAP, BMP and Wnt signals. Lastly, a radial chemical gradient generation device integrated with the micropatterning platform will be developed to interrogate whether biochemical gradient can also induce cell spatial patterning during neural induction, and whether cell shape and force act downstream of biochemical gradient or work independently to determine lineage specification. Using integrative microsystems with the capability to fine-tune chemical and mechanical environment, this research provides for the first time a quantitative analysis of the interactions between biochemical and biomechanical cues in neural development.

神经管缺陷是最常见的先天缺陷之一，每年在全球范围内影响超过500,000名婴儿。神经管缺陷会导致严重的健康问题，包括腿部瘫痪，脑损伤甚至死亡。为了开发用于预防和诊断神经管缺陷的新方法，需要对中枢神经系统发展的基本理解。使用动物模型，调节神经诱导的遗传和生化因子（中枢神经系统发育的第一阶段）已部分揭示。最近的研究表明，神经诱导中的细胞命运决策受生物力学提示调节。 这种机械机制的理解很少，并且使用动物模型很难研究。这项研究将建立一系列新型细胞培养工具，以研究神经诱导过程中的遗传，生化和生物力学相互作用。这些新工具将提供具有较低成本的实验，而不使用动物受试者来确定对神经管形成的机械影响的能力。将收集有关细胞的机械环境如何改变神经管发育过程中其行为的基本数据。 首席研究人员将与K-12互动，本科生和研究生具有不同的种族背景和性别，并通过这项跨学科的生物工程学研究，并鼓励他们从事科学和工程职业。该项目将测试机械相互作用在神经发展中决定形态发生事件的假说。已知微图案细胞培养环境会导致人类细胞模仿神经上皮细胞和神经板的神经板界细胞的空间模式，因此将用于模拟神经诱导。药物处理和一种新的装置，该设备在局部扩展了微图指定区域中的细胞，以动态调节细胞形状和力，以研究体外神经诱导中的细胞空间模式如何调节细胞形状和力。将研究神经诱导中的机械传导途径，重点是YAP，BMP和WNT信号的功能参与。最后，将开发与微观平台集成的径向化学梯度生成装置，以询问生化梯度是否还可以在神经诱导过程中诱导细胞空间模式，以及细胞形状和力的生化梯度下游还是在独立工作以确定谱系规范的下游。使用整合微型系统，具有微调化学和机械环境的能力，这项研究首次提供了对神经发育中生化和生物力学线索之间相互作用的定量分析。