Sonogenetic Remote Control of Cellular Function

细胞功能的声遗传学远程控制

• 批准号: 10261864
• 负责人: Mikhail Shapiro
• 金额: $ 117.25万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10261864
• 关键词: Acoustics; Anatomy; Animals; Biological; Biological Phenomena; Biology; Biosensor; Brain region; Cell Therapy; Cell physiology; Cells; Communication; Deposition; Development; Engineering; Fluorescence Microscopy; Focused Ultrasound; Gastrointestinal tract structure; Gene Expression; Goals; Human body; Image; Immune; Immunotherapy; Investigation; Light; Location; Mechanics; Medical Imaging; Medical Technology; Methods; Modality; Neurons; Neurosciences; Operative Surgical Procedures; Optics; Pathway interactions; Penetration; Physics; Process; Property; Proteins; Reporter Genes; Research; Research Personnel; Signal Transduction; Structure; Techniques; Technology; Time; Tissues; Travel; Tumor-infiltrating immune cells; Ultrasonography; Visible Radiation; Work; biological systems; cellular imaging; in vivo; mechanical force; microbial colonization; molecular imaging; neuroregulation; optogenetics; receptor; remote control; sound; tool; tumor

SUMMARY The discovery and development of fluorescent proteins and optogenetics revolutionized biology by making it possible to image and control specific cellular processes with visible light. While these tools have enabled countless biological discoveries, the poor penetration of light into living tissue makes it difficult to use optical techniques in intact animals. As a result, biological phenomena ranging from the signaling of neurons in deep- brain regions, to the infiltration of immune cells into tumors, to the microbial colonization of the GI tract, are challenging to study within their natural in vivo context. If instead of light it were possible to visualize and manipulate cellular function using a more penetrant form of energy such as ultrasound, this would open previously inaccessible domains of in vivo biology to direct investigation. In addition, it would enhance the development of cell-based therapies by allowing cellular agents to be seen and controlled after administration into the human body. The physics of ultrasound make it an ideal modality for deep-tissue cellular communication. Sound waves in the MHz range are weakly scattered by tissue and can therefore penetrate several cm into the body. With wavelengths on the order of 100 µm and travel times < 1 ms, ultrasound can access many key structures and processes. When focused, sound waves can deliver mechanical and thermal energy to precise anatomical locations. These properties have already made ultrasound one of the world’s most widely used technologies for medical imaging and non-invasive surgery. However, the potential of ultrasound to serve as a tool for cellular imaging and control has been relatively untapped due to a lack of methods to connect it to the function of specific cells and biomolecules. In previous work, the Shapiro lab has pioneered the use of ultrasound in cellular and molecular imaging by developing the first acoustic reporter genes and biosensors for ultrasound, aiming to “do for ultrasound what fluorescent proteins have done for fluorescence microscopy”. The major goal of our proposed new research direction is to “do for ultrasound what optogenetics has done for light” by giving sound waves the ability to control specific cellular functions such as neuronal excitation, gene expression and intracellular signaling in vivo. The basic principle of our approach is to (1) use focused ultrasound to deposit acoustic energy at a specific location in tissue, (2) use genetically encoded “acoustic antennae” to convert this energy into local mechanical force, and (3) use this force to actuate mechanosensitive receptors to produce specific cellular signals. We will implement this approach in neurons and immune cells to enable unique neuroscience and cell therapy applications. If successful, this work will help establish the new field of sonogenetics by providing researchers and clinicians with the unprecedented ability to “point and click” on cells deep within the body and tell them what to do.

概括 荧光蛋白和光遗传学的发现和开发通过使生物学彻底改变了生物学 可以用可见光来形象和控制特定的蜂窝过程。这些工具已启用 无数的生物学发现，光渗透到活组织中的不良渗透使得很难使用光学 完整动物的技术。结果，生物学现象范围从深处神经元的信号传导 脑区域将免疫细胞浸润到肿瘤中，gi段的微生物定植是 在其自然体内背景下学习的挑战。如果不是光，则可以看到和 使用更渗透的能量（例如超声）操纵细胞功能，这将打开 以前在体内生物学领域无法直接研究。另外，它将增强 通过允许在给药后看到和控制细胞剂来开发基于细胞的疗法 进入人体。超声的物理学使其成为深度组织蜂窝通信的理想方式。 MHz范围内的声波被组织薄弱，因此可以穿透几cm 身体。超声波的波长为100 µm，旅行时间<1 ms，可以访问许多键 结构和过程。当聚焦时，声波可以将机械和热能传递至精确 解剖位置。这些属性已经使超声波成为世界上最广泛使用的 医学成像和非侵入性手术的技术。但是，超声波的潜力 由于缺乏将其连接到的方法，用于蜂窝成像和控制的工具已相对尚未开发 特定细胞和生物分子的功能。在以前的工作中，Shapiro Lab开创了超声的使用 在细胞和分子成像中，通过开发第一个声学报告基因和生物传感器以进行超声， 旨在“超声检查荧光显微镜为荧光蛋白所做的事情”。主要目标 我们拟议的新研究方向是“超声波遗传学为光造成的光线做到的。” 声波控制特定细胞功能的能力，例如神经元兴奋，基因表达和 体内细胞内信号传导。我们方法的基本原理是（1）使用集中的超声来存入 在组织中特定位置的声能，（2）使用遗传编码的“声触角”来转换这一点 能量进入局部机械力，（3）使用此力激活机械接收器以产生 特定的细胞信号。我们将在神经元和免疫细胞中实施这种方法，以实现独特 神经科学和细胞治疗应用。如果成功，这项工作将有助于建立新领域 通过为研究人员和临床医生提供前所未有的“指向和点击”细胞的能力来发声。 在身体内部深处，告诉他们该怎么做。