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.

摘要