Acoustothermogenetics for Cell Engineering

摘要 基于荧光共振能的荧光蛋白及其衍生生物传感器 转移(FRET)通过使动态分子可视化而使生物学/医学发生革命性变化 具有高时空分辨率的活细胞中的活动。光遗传学使微扰 然而，生命系统中的特定分子事件，缺乏操纵细胞和 身体深处的组织。我在这里建议发展声热遗传学作为一种普遍的方法来允许 直接、远程控制、非侵入性地操纵人体深部部位的活细胞功能 病理过程的纠正和特定治疗干预的控制。我会先来 设计分子传感器和基因传感器，使工程细胞能够感知 超声波信号直接并转化为基因激活以产生所需的蛋白质 监管者。然后我将使用基于细胞的免疫疗法，特别是嵌合抗原受体(CAR)- 以表达T细胞为初步试验目标，建立原则上实用的这一新方法。 CAR-T免疫疗法正在成为癌症治疗的一种范式转变的治疗方法，但 它的广泛应用面临着重大挑战。我建议开发对超声波敏感的CAR-T细胞用于 他们通过超声波换能器进行远距离控制，以靶向并根除实体肿瘤。最后，我会 将这种远程控制的声热遗传学方法扩展到开发一个通用系统，该系统将 原则上允许控制活细胞中用于重新编程的任何遗传或表观遗传调节 在活体情况下的细胞功能。这种方法应该允许远程控制的单元 以非侵入性方式进行高时空精度的激活，用于广泛的治疗 申请。这种新的方法还应该提供一个通用的范例来动态控制 生物学研究和临床应用的分子和细胞功能。

Abstract Fluorescent proteins (FPs) and their derived biosensors based on fluorescence resonance energy transfer (FRET) have revolutionized biology/medicine by allowing the visualization of dynamic molecular activities in live cells with high spatiotemporal resolutions. Optogenetics has enabled the perturbation of specific molecular events in living systems, however, there is a lack of methods to manipulate cells and tissues deep in the body. I propose here to develop acoustothermogenetics as a general method to allow the direct, remotely-controlled, non-invasive manipulation of live cell functions in deep body sites for the correction of pathological processes and the control of specific therapeutic interventions. I will first engineer molecular sensors and genetic transducers which will allow the engineered cell to perceive the ultrasound signals directly and transduce them into genetic activation for the production of desired protein regulators. I will then use cell-based immunotherapy, particularly chimeric antigen receptor (CAR)- expressing T cells, as my initial test target to establish, in principle, the practical utility of this new method. CAR-T immunotherapy is becoming a paradigm-shifting therapeutic approach for cancer treatment, but its broad application has major challenges. I propose to develop ultrasound-sensitive CAR-T cells for their control from a distance by ultrasound transducers to target and eradicate solid tumors. Lastly, I will extend this remotely-controlled acoustothermogenetics approach to develop a general system that would allow the control of, in principle, any genetic or epigenetic modulation in live cells for the reprogramming of cellular functions under in vivo situation. This approach should allow the remotely-controlled cell activation with a high spatiotemporal precision in a non-invasive manner for a broad range of therapeutic applications. This novel approach should also provide a general paradigm to dynamically control molecular and cellular functions for biological studies and clinical applications.