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性疾病。这些技术之所以可能，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，但化学信号也会干扰正常的细胞新陈代谢。该项目将开发一种对磁信号做出反应的替代生物控制系统。为本科生提供的研究机会将培养一支熟练的STEM劳动力队伍。将通过为K-12教师和高中生举办为期8周的暑期讲习班，扩大外联工作。将评估通过静磁场和交变/振荡磁场远程激活基因，以控制哺乳动物细胞和细胞培养中的蛋白质表达。需要检验的核心假设是，磁场可以通过与离子通道捆绑的铁蛋白的共表达和中介来诱导离子通道的开放。铁蛋白纳米颗粒将作为换能器，将磁信号转化为物理信号，从而激活信号级联。与化学信号相比，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，阐明了静磁场和振荡/交变磁场诱导离子通道激活的机制。第二，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，以增强铁蛋白的特性，从而导致瞬时受体电位(Trp)通道门控。第三，作为生物工程的应用，使用基因编码的Trp通道-铁蛋白系统来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作为设计方法的基础，以控制生物制造应用中的细胞信号、基因转录和蛋白质表达/生产。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.