Acoustothermogenetics for Cell Engineering

细胞工程的声热遗传学

• 批准号: 10825009
• 负责人: Yingxiao Wang
• 金额: $ 35.33万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10825009
• 关键词: Acoustothermogenetics; Cell; Engineering

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.

抽象的 荧光蛋白（FPS）及其基于荧光共振能的衍生生物传感器 转移（FRET）通过允许动态分子的可视化彻底改变了生物学/医学 具有高时空分辨率的活细胞中的活性。光遗传学使 但是，在生命系统中的特定分子事件，但是缺乏操纵细胞的方法 组织深处的组织。我在这里提议开发声学上的质学作为一种通用方法，以允许 直接的，远程控制的，无创的无创操作对深层身体部位的活细胞功能 纠正病理过程和特定治疗干预措施的控制。我会首先 工程师的分子传感器和遗传传感器将使工程细胞能够感知 超声信号直接并将其转换为遗传激活，以产生所需蛋白质 监管机构。然后，我将使用基于细胞的免疫疗法，尤其是嵌合抗原受体（CAR） - 表达T细胞，是我最初的测试目标，原则上是这种新方法的实际实用性。 CAR-T免疫疗法正成为一种癌症治疗的范式转移治疗方法，但 它的广泛应用有重大挑战。我建议开发对超声敏感的CAR-T细胞 它们从超声传感器从距离进行控制到靶标和根除实体瘤。最后，我会的 扩展这种远程控制的声热估计方法，以开发一种通用系统 原则上允许在活细胞中控制任何遗传或表观遗传调制以进行重编程 在体内情况下的细胞功能。这种方法应允许远程控制的单元格 以非侵入性的方式激活高时空精度，以进行广泛的治疗 申请。这种新颖的方法还应提供一般的范式来动态控制 用于生物学研究和临床应用的分子和细胞功能。