Biogenic Gas Nanostructures As Molecular Imaging Reporters For Ultrasound

生物气体纳米结构作为超声分子成像记者

• 批准号: 10318929
• 负责人: Mikhail Shapiro
• 金额: $ 65.38万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318929
• 关键词: Achievement; Acoustics; Address; Area; Bacteria; Biochemical; Biological; Biology; Biosensor; Blood Circulation; Cell physiology; Cells; Chemicals; Contrast Media; Detection; Development; Diagnostic; Dimensions; Elements; Engineering; Escherichia coli; Event; Extravasation; Frequencies; Gases; Gastrointestinal tract structure; Gene Expression; Genetic; Genetic Engineering; Goals; Image; Imaging technology; Laboratories; Magnetic Resonance Imaging; Malignant Neoplasms; Mammalian Cell; Medicine; Metalloproteases; Methods; Microbe; Microscopy; Modality; Modeling; Molecular; Molecular Target; Multimodal Imaging; Mus; Nanostructures; Nature; Optics; Physiologic pulse; Predisposition; Property; Proteins; Reporter; Reporter Genes; Research; Resolution; Role; Salmonella typhimurium; Sensitivity and Specificity; Signal Transduction; Surface Properties; Techniques; Technology; Therapeutic Agents; Tissues; Transplantation; Ultrasonography; Vesicle; Work; analog; base; biological research; biomedical imaging; cellular imaging; cellular targeting; commensal bacteria; cost; design; enzyme activity; extracellular; imaging agent; imaging modality; in vivo; innovation; insight; microbiome; molecular diagnostics; molecular imaging; multicatalytic endopeptidase complex; multidisciplinary; multiplexed imaging; nano; nanoscale; non-invasive imaging; pressure; programs; research and development; response; sensor; signal processing; success; synthetic biology; targeted imaging; temporal measurement; tumor; tumor xenograft; ultrasound; uptake

PROJECT SUMMARY/ABSTRACT Ultrasound is among the world's most widely used biomedical imaging technologies due to its relative simplicity, low cost and ability to visualize deep tissues with high spatial and temporal resolution. However, ultrasound has historically had a small role in molecular and cellular imaging due to the lack of contrast agents connected to specific aspects of cellular function such as gene expression. To address this limitation, we are developing the first acoustic biomolecules – proteins that can be imaged with ultrasound. These constructs are based on gas vesicles – a unique class of gas-filled proteins from buoyant photosynthetic microbes, which we adapted as imaging agents for ultrasound in 2014. Since this key initial discovery, our laboratory has led the development of the emerging field of biomolecular ultrasound by engineering the physical, chemical and biological properties of gas vesicles to enable multiplexed imaging, cellular targeting and selective detection in vivo. In parallel, we have worked on transplanting the genetic program encoding gas vesicles into heterologous hosts, recently succeeding in doing so in commensal bacteria relevant to the mammalian microbiome, while in parallel making initial progress on expressing gas vesicles in mammalian cells. In addition, we discovered that gas vesicles can produce susceptibility-weighted MRI contrast erasable by ultrasound, providing an additional readout modality with unique advantages. Here we propose to build on these insights to advance gas vesicles as targeted nanoscale contrast agents, mammalian reporter genes and functional sensors for ultrasound. This work will focus on engineering gas vesicle properties for long-term circulation and extravascular targeting through the bloodstream, achieving robust expression of gas vesicles as reporter genes in mammalian cells, developing nonlinear ultrasound pulse sequences to maximize the sensitivity of gas vesicle imaging, and designing the first acoustic sensors of enzyme activity. The fundamental innovation contained in this research is that gas vesicle are the first biomolecular, genetically engineered and encoded contrast agent of any kind for ultrasound. As a result, they have the potential to transform this imaging modality analogously to the way fluorescent proteins transformed optical microscopy.

项目摘要/摘要 由于其相对，超声是世界上最广泛使用的生物医学成像技术之一 简单，低成本和能够以高空间和临时分辨率可视化深度时间。然而， 由于缺乏对比剂，超声在历史上历史上具有很小的作用在分子和细胞成像中 连接到细胞功能的特定方面，例如基因表达。为了解决这个限制，我们是 开发第一个可以用超声成像的蛋白质的蛋白质。这些结构是 基于燃气蔬菜 - 一种独特的来自浮力微生物的充气蛋白质，我们是我们的 改编为2014年超声检查的成像剂。由于这一关键最初发现，我们的实验室领导了 通过设计物理，化学和 气体蔬菜的生物学特性，以实现多路复用成像，细胞靶向和选择性检测 体内。同时，我们一直致力于将编码加油蔬菜的遗传程序移植到异源 寄主，最近成功地从事与哺乳动物微生物组相关的共生细菌 并行在哺乳动物细胞中表达燃气蔬菜的初步进展。此外，我们发现 燃气蔬菜可以通过超声擦除的易感加权MRI对比度，提供额外的 读取方式具有独特的优势。在这里，我们建议以这些见解为基础，以促进加油蔬菜 作为靶向的纳米级对比剂，超声波的哺乳动物记者基因和功能传感器。这 工作将集中于工程气囊泡特性，用于长期循环和血管外靶向 通过血液，通过哺乳动物细胞中的燃气蔬菜作为报告基因的强劲表达， 开发非线性超声脉冲序列，以最大程度地提高气囊成像的灵敏度，并 设计酶活性的第一个声传感器。这项研究中包含的基本创新 是气囊是任何类型的生物分子，一般设计和编码的对比剂 超声波。结果，它们有可能将这种成像方式类似地转换为方式 荧光蛋白转化了光学显微镜。