Imaging bacterial infection using deuterium-enriched sugar alcohols.

使用富含氘的糖醇对细菌感染进行成像。

• 批准号: 10316810
• 负责人: David M Wilson
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316810
• 关键词: Address; Bacteria; Bacterial Infections; Biological; Bioreactors; Cell Line; Cell Nucleus; Cells; Chemicals; Child; Clinical; Controlled Environment; Detection; Deuterium; Diagnosis; Engineering; Ethanol; Fever; Frequencies; Goals; Gram-Negative Bacteria; Human; Human body; Hydrogen; Image; Imaging Device; Imaging Techniques; Imaging technology; Immune; Immune response; In Vitro; Infection; Inflammatory; Ionizing radiation; Laboratories; Leukocytes; Magnetic Resonance Imaging; Malignant Neoplasms; Mammalian Cell; Mannitol; Measures; Metabolic; Metabolism; Methodology; Methods; Modeling; Morphology; Mus; Myositis; Nuclear Magnetic Resonance; Nutrient; Organism; Patients; Physicians; Positron-Emission Tomography; Procedures; Process; Radial; Reproducibility; Route; Scanning; Sorbitol; Specificity; Spectrum Analysis; Sugar Alcohols; System; Technology; Testing; Time; Tissue Sample; Variant; Vulnerable Populations; Water; adduct; analog; bacterial metabolism; cancer cell; clinical translation; detection limit; fluorodeoxyglucose; human tissue; imaging approach; imaging detection; imaging modality; in vivo; in vivo imaging; metabolic abnormality assessment; metabolic imaging; microorganism; novel; pathogen; pathogenic bacteria; radiologist; recruit; response; single photon emission computed tomography; stable isotope; sugar; three dimensional cell culture; tool

PROJECT SUMMARY: This application addresses a major challenge that radiologists and other physicians encounter frequently, namely distinguishing active infection from other processes in the human body. In response to this challenge, our laboratory has developed both hyperpolarized 13C MRI and positron emission tomography (PET) tools targeting bacteria-specific metabolism. In this proposal, we employ another nuclear magnetic resonance (NMR)-observable stable isotope namely deuterium (2H) to detect living microorganisms both in vitro and in vivo. In doing so we address two major challenges of 2H magnetic resonance imaging (MRI) by (1) identifying 2H MRI-observable metabolites that have the needed chemical shift separation from HDO (water) and (2) using bacteria-specific sugar alcohols whose incorporation into microorganisms is not easily saturated. Our approach also takes advantage of two different strategies to incorporate 2H in a microorganism-specific way, and newly developed 2H MRI methods to maximize sensitivity. The two detection strategies pursued are either (1) a 2H substrate is converted to a dominant, 2H-MRI observable downstream metabolite or (2) a 2H substrate is converted to a dead-end metabolite that is accumulated as a 2H-MRI detectable species. These two concepts are highlighted by enriched variants of sorbitol, either D-[6,6'-2H2]sorbitol whose metabolism may be detected by its conversion to lactate/ethanol, or 2-deoxy-D-[2,2'-2H2]sorbitol anticipated to be “trapped” as its 6-phosphorylated adduct in bacteria. In both cases, the 2H nuclei have the needed chemical shift for in vivo 2H MRI imaging. In addition, the technologies pursued are amenable to clinical translation; our long-term goal is application of nontoxic 2H sugar alcohols to vulnerable populations including children, without the need for ionizing radiation. We will first adapt an NMR- compatible bioreactor for use in investigating 2H substrate metabolism in bacteria in vitro (Specific Aim 1). We will show then show bacteria-specific incorporation of 2H using enriched substrates, that are either metabolized to dominant 2H-MRI detectable products, or retained as dead-end molecules by pathogens (Specific Aim 2). In Specific Aim 3, we will show that 2H MRI at 14T using these tools can detect living bacteria in vivo.

项目摘要： 该应用程序解决了放射性医师和其他医生经常遇到的重大挑战， 即将主动感染与人体其他过程区分开。为了应对这一挑战， 我们的实验室已经开发了超极化的13C MRI和二极管发射断层扫描（PET）工具 靶向细菌特异性代谢。在此提案中，我们会雇用另一个核磁共振 （NMR） - 可观察的稳定同位素，即氘（2H），以检测体外和IN的活体微生物 体内。在此过程中，我们通过（1）识别2H磁共振成像（MRI）的两个主要挑战 2H MRI观察的代谢产物具有所需的化学位移与HDO（水）和（2）的分离 细菌特异性的糖醇的保险不容易饱和。我们的方法 还利用两种不同的策略以特定于微生物的方式合并2H 开发了2H MRI方法，以最大程度地提高灵敏度。 提出的两种检测策略要么（1）2H基材转换为主要的2H-MRI 可观察到的下游代谢物或（2）2H底物转换为死末端代谢产物 积聚为2H-MRI可检测物种。这两个概念由丰富的变体突出显示 山梨糖醇，d- [6,6'-2H2]山梨糖醇，其代谢可以通过转换为裂解/乙醇来检测 2-脱氧-D- [2,2'-2H2]山梨糖醇预计将被“捕获”为细菌中的6磷酸化加合物。在这两个中 病例，2H核心具有体内2H MRI成像所需的化学位移。此外，这些技术 追求适合临床翻译；我们的长期目标是将无毒2H糖醇应用于 包括儿童在内的脆弱人群，无需电离辐射。我们将首先适应NMR- 兼容的生物反应器用于研究体外细菌中2H底物代谢的2H（特定目标1）。 我们将使用富集的底物显示2H的细菌特异性掺入2H 代谢为主要的2H-MRI可检测产物，或者被病原体保留为死前分子 （特定目标2）。在特定目标3中，我们将证明使用这些工具在14T时2H MRI可以检测到生活 体内细菌。