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.

项目概要/摘要 超声波是世界上使用最广泛的生物医学成像技术之一，因为它的相对 简单、成本低并且能够以高空间和时间分辨率可视化深层组织。 由于缺乏造影剂，超声波历来在分子和细胞成像中发挥的作用很小 与细胞功能的特定方面（例如基因表达）相关。为了解决这一限制，我们正在研究。 开发第一个声学生物分子——可以用超声波成像的蛋白质。 基于气体囊泡——一种来自浮力光合微生物的独特的充满气体的蛋白质，我们将其 2014 年用作超声显像剂。自从这一关键的初步发现以来，我们的实验室一直引领着 通过物理、化学和工程技术的发展，生物分子超声这一新兴领域的发展 气体囊泡的生物学特性，可实现多重成像、细胞靶向和选择性检测 与此同时，我们还致力于将编码气体囊泡的遗传程序移植到异源体内。 最近在与哺乳动物微生物组相关的共生细菌中成功地做到了这一点，同时 与此同时，我们在哺乳动物细胞中表达气体囊泡方面取得了初步进展。 气体囊泡可以产生可通过超声波擦除的磁化率加权 MRI 对比，从而提供额外的 在这里，我们建议以这些见解为基础来推进气体囊泡的发展。 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。 工作重点是设计气泡特性以实现长期循环和血管外靶向 通过血流，在哺乳动物细胞中实现气体囊泡作为报告基因的稳健表达， 开发非线性超声脉冲序列以最大限度地提高气体囊泡成像的灵敏度，以及 设计第一个酶活性声学传感器是本研究的根本创新。 气囊是第一个生物分子、基因工程和编码的造影剂 因此，他们有可能像超声波一样改变这种成像方式。 荧光蛋白改变了光学显微镜。