Acoustothermogenetics for Cell Engineering

摘要 荧光蛋白（FP）及其衍生的基于荧光共振能量的生物传感器 荧光共振能量转移（FRET）已经通过允许动态分子的可视化而彻底改变了生物学/医学 活细胞中的活动具有高时空分辨率。光遗传学已经能够干扰 然而，在生命系统中的特定分子事件中，缺乏操纵细胞的方法， 身体深处的组织。我在这里建议发展声热发生学作为一种通用方法， 直接，远程控制，非侵入性操纵体内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 设计分子传感器和遗传转换器，使工程细胞能够感知 超声信号直接并将其转化为基因激活以产生所需的蛋白质 监管部门然后，我将使用基于细胞的免疫疗法，特别是嵌合抗原受体（CAR）- 表达T细胞，作为我最初的测试目标，原则上，建立这种新方法的实用性。 CAR-T免疫疗法正在成为癌症治疗的范式转变治疗方法， 其广泛应用面临重大挑战。我建议开发超声敏感的CAR-T细胞， 它们通过超声换能器从远处控制以靶向和根除实体肿瘤。最后，我将 扩展这种远程控制的声热发生学方法，以开发一种通用系统， 原则上允许控制活细胞中用于重编程的任何遗传或表观遗传调节 在体内情况下的细胞功能。这种方法可以让远程控制的细胞 以非侵入性方式以高时空精度激活，用于广泛的治疗 应用.这种新颖的方法还应该提供一个通用的范例，以动态控制 用于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.