Acoustothermogenetics for Cell Engineering

细胞工程的声热遗传学

• 批准号: 10413031
• 负责人: Yingxiao Wang
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413031
• 关键词: Biological Process; Biology; Biosensor; Cell physiology; Cells; Cellular immunotherapy; Disease; Engineering; Epigenetic Process; Event; Fluorescence Resonance Energy Transfer; Genes; Genetic; Immunotherapy; Medicine; Methods; Molecular; Organism; Pathologic Processes; Production; Proteins; Protocols documentation; Resolution; Signal Transduction; Site; Solid Neoplasm; System; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transducers; Ultrasonic Transducer; Visualization; base; cancer therapy; cellular engineering; chimeric antigen receptor; chimeric antigen receptor T cells; clinical application; epigenetic regulation; in vivo; novel strategies; optogenetics; receptor expression; sensor; spatiotemporal; ultrasound

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（FP）及其衍生的基于荧光共振能量的生物传感器 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活动。光遗传学使得扰动成为可能 然而，缺乏操纵细胞和生命系统中特定分子事件的方法 身体深处的组织。我在这里建议开发声热遗传学作为一种通用方法，以允许 对深部身体部位的活细胞功能进行直接、远程控制、非侵入性操作 纠正病理过程和控制特定的治疗干预措施。我会先 设计分子传感器和遗传传感器，使工程细胞能够感知 直接超声信号并将其转化为基因激活以产生所需的蛋白质 监管机构。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，作为我的初步测试目标，原则上确定这种新方法的实际用途。 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，但是 其广泛应用面临重大挑战。我建议开发超声波敏感的 CAR-T 细胞 他们通过超声波换能器进行远距离控制，以瞄准并根除实体瘤。最后，我会 扩展这种远程控制的声热遗传学方法来开发一个通用系统 原则上允许控制活细胞中的任何遗传或表观遗传调节以进行重编程 体内情况下的细胞功能。这种方法应该允许远程控制单元 以非侵入性方式以高时空精度激活，用于广泛的治疗 应用程序。这种新颖的方法还应该提供一个动态控制的通用范例 用于生物学研究和临床应用的分子和细胞功能。