Collaborative Research: Elucidating the Mechanism of Magnetogenetics for Remote Activation of Cell Function

合作研究：阐明磁遗传学远程激活细胞功能的机制

• 批准号: 1930163
• 负责人: Jonathan Dordick
• 金额: $ 30万
• 依托单位: Rensselaer Polytechnic Institute
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1930163&HistoricalAwards=false
• 关键词: Collaborative; Research; Elucidating; Mechanism; Magnetogenetics

We are entering a new age of manufacturing where living cells are used to produce fuels, chemicals, and therapeutic proteins. Cell therapies offer the promise of enhancing a patient's natural immune system cells to fight cancer and other metabolic diseases. These technologies are possible because of our ability to control the metabolism of cells. Most of the currently used control methods rely on chemical signaling, but chemical signals can also interfere with normal cell metabolism. This project will develop a alternate biological control system that responds to magnetic signals. Research opportunities for undergraduates will develop a skilled STEM workforce. Outreach efforts will be multiplied through development of an 8-week summer workshop for K-12 teachers and high school students. Remote gene activation through static and alternating/oscillating magnetic fields will be evaluated for the control of protein expression in mammalian cells and cell cultures. The core hypothesis to be tested is that magnetic fields can induce the opening of ion channels upon co-expression of and mediation by ferritin tethered to the ion channel. The ferritin nanoparticles would serve as transducers, converting magnetic signals into physical ones that can activate a signal cascade. Magnetic fields offer much finer temporal and spatial control than is available using chemical signaling. The scope of the project and specific activities are threefold. First, elucidate the mechanism of static and oscillating/alternating magnetic field induced activation of ion channels. Second, tune sensitivity and responsiveness of magnetically activated ion channels by constructing genetic systems and controlling cell culture conditions to enhance ferritin properties leading to transient receptor potential (TRP) channel gating. Third, as a bioengineering application, use the genetically-encoded TRP channel-ferritin system to remotely control gene transcription and induce expression of key proteins involved in neurogenesis. The outcome of this study could be a foundation for designing methods to control cellular signaling, gene transcription, and protein expression/production for biomanufacturing applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

我们正在进入一个新的制造时代，活细胞被用来生产燃料、化学品和治疗性蛋白质。细胞疗法有望增强患者的天然免疫系统细胞，以对抗癌症和其他代谢性疾病。 这些技术之所以成为可能，是因为我们有能力控制细胞的新陈代谢。目前使用的控制方法大多依赖于化学信号传导，但化学信号也会干扰正常的细胞代谢。 该项目将开发一种响应磁信号的替代生物控制系统。本科生的研究机会将培养一支熟练的 STEM 劳动力队伍。通过为 K-12 教师和高中生举办为期 8 周的夏季讲习班，我们将加大宣传力度。将评估通过静态和交变/振荡磁场的远程基因激活来控制哺乳动物细胞和细胞培养物中的蛋白质表达。要测试的核心假设是，磁场可以在与离子通道相连的铁蛋白的共表达和介导下诱导离子通道的打开。铁蛋白纳米粒子将充当传感器，将磁信号转换为可以激活信号级联的物理信号。与使用化学信号传导相比，磁场提供了更精细的时间和空间控制。该项目的范围和具体活动有三个方面。首先，阐明静态和振荡/交变磁场诱导离子通道激活的机制。其次，通过构建遗传系统和控制细胞培养条件来调整磁激活离子通道的敏感性和响应性，以增强铁蛋白特性，从而导致瞬时受体电位（TRP）通道门控。第三，作为生物工程应用，利用基因编码的TRP通道-铁蛋白系统远程控制基因转录并诱导参与神经发生的关键蛋白的表达。这项研究的结果可以为设计用于生物制造应用的控制细胞信号传导、基因转录和蛋白质表达/生产的方法奠定基础。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优点和技术进行评估，被认为值得支持。更广泛的影响审查标准。