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

我们正在进入一个新的制造业时代，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自然免疫系统细胞，以对抗癌症和其他代谢疾病。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。目前使用的大多数控制方法依赖于化学信号，但化学信号也会干扰正常的细胞代谢。该项目将开发一种对磁信号作出反应的替代生物控制系统。本科生的研究机会将培养熟练的STEM劳动力。通过为K-12教师和高中生开展为期8周的暑期讲习班，将扩大推广工作。将评估通过静态和交变/振荡磁场远程激活基因，以控制哺乳动物细胞和细胞培养物中的蛋白质表达。要验证的核心假设是，磁场可以通过拴在离子通道上的铁蛋白的共表达和介导诱导离子通道的打开。铁蛋白纳米颗粒将充当换能器，将磁信号转换为可以激活信号级联的物理信号。磁场提供了比化学信号更好的时间和空间控制。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节磁激活离子通道的灵敏度和响应性，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，利用遗传编码的TRP通道-铁蛋白系统远程控制基因转录，诱导神经发生关键蛋白的表达。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。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.