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.

项目总结/摘要 超声波是世界上最广泛使用的生物医学成像技术之一，由于其相对于 简单性、低成本和以高空间和时间分辨率可视化深部组织的能力。然而，在这方面， 由于缺乏造影剂 与细胞功能的特定方面如基因表达有关。为了解决这个问题，我们 开发第一种声学生物分子--可以用超声成像的蛋白质。这些构建体 基于气体囊泡-一种来自浮力光合微生物的独特的充气蛋白质，我们 在2014年被用作超声成像剂。自从这一关键的初步发现以来，我们的实验室已经领导了 通过工程化的物理，化学和生物分子超声的新兴领域的发展， 气体囊泡的生物学性质，以使得能够进行多重成像、细胞靶向和选择性检测， vivo.与此同时，我们已经致力于将编码气体囊泡的遗传程序移植到异源细胞中， 宿主，最近成功地在与哺乳动物微生物组相关的肠道细菌中这样做，而在 同时，在哺乳动物细胞中表达气体囊泡方面也取得了初步进展。另外，我们发现， 气泡可以产生可被超声消除的磁共振成像对比度，提供额外的 具有独特优势的读出模式。在这里，我们建议建立在这些见解，以推进气体囊泡 作为靶向纳米级造影剂、哺乳动物报告基因和超声功能传感器。这 工作将集中在长期循环和血管外靶向的工程气泡特性上 通过血流，在哺乳动物细胞中实现作为报告基因的气泡的稳健表达， 开发非线性超声脉冲序列以最大化气泡成像的灵敏度，以及 设计了第一个酶活性声学传感器。这项研究的基本创新之处在于 气体囊泡是第一种生物分子、基因工程和编码造影剂， 超声.因此，他们有潜力将这种成像方式类似于 荧光蛋白改变了光学显微镜。