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PET imaging of viral infection

病毒感染的 PET 成像

基本信息

批准号：
10437002
负责人：
Zhenghong Lee
金额：
$ 24.15万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437002
关键词：
2019-nCoV Acute Lung Injury Affect Biological Assay Blood Vessels COVID-19 Cardiac Catabolism Cells Chest Clinical Clinical Management Complement Consumption Coronavirus Coronavirus Infections Cytomegalovirus DNA Viruses Disease Dose Encephalomyelitis Etiology Evaluation Ferrets Fluorine Fluorouracil Future Genome Goals Gold Hepatitis Herpesviridae Human Human Herpesvirus 4 Image Imaging Device Imaging Techniques Immune Immunocompetent Infection Inflammatory Response Injections Interphase Cell Isotopes Kidney Label Learning Life Style Lung diseases Malignant neoplasm of gastrointestinal tract Measures Messenger RNA Metabolism Modeling Monitor Morbidity - disease rate Murine hepatitis virus Mus Natural History Nucleosides Nucleotides Organ Pathway interactions Perception Positron-Emission Tomography Prodrugs RNA RNA Viruses RNA chemical synthesis RNA-Directed RNA Polymerase Radio Radiolabeled Rattus Respiratory Disease SARS-CoV-2 infection Site Structure System Testing Therapeutic Time TimeLine Tissues Tracer Uracil Uracil phosphoribosyltransferase Uridine Uridine Monophosphate Validation Viral Viral Physiology Viral hepatitis Virus Virus Diseases Virus Replication X-Ray Computed Tomography antiviral drug development base clinical application clinically relevant disease phenotype enteritis experience experimental study gastrointestinal genomic RNA human coronavirus imaging approach in vivo microPET mortality mouse model novel nucleobase nucleoside monophosphate nucleotide metabolism pre-clinical prevent protective effect pyrimidine metabolism remdesivir respiratory therapeutic candidate time use tool treatment duration tripolyphosphate tumor uptake uracil analog viral RNA viral genomics

项目摘要

Many viruses sustain a parasitic lifestyle by exploiting host cell supplies of nucleotides for replication. The manifestation and progression of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 (SARS2), an RNA virus, is accompanied by the expansion of the virus in the infected host using host's machinery. The rapid SARS2 expansion requires augmented RNA synthesis via the salvage pathway of RNA synthesis, most especially in the non-dividing cells that are the targets of SARS2 infection. This provides an opportunity to trace the status of viral infection if an imaging tracer that is indicative of viral RNA synthesis is available. Similar to the host, viral related RNA synthesis (viral genomic RNA or viral messenger RNA) occurs in three stages: initiation, elongation and termination. We will focus on the elongation of viral related RNA synthesis, which is the repeated addition of a nucleoside monophosphate (NMP) to the 3’ end of the growing RNA chain. Since SARS2 requires massive amounts of host cell uridine, 1/3 of its genome is uridine, uridine is moreover required for sub-genome positive strand RNA synthesis/viral function. Accordingly, radiolabeled uridine shall be used to track pyrimidine metabolism by PET imaging for augmented RNA synthesis under SARS2 infection. However, the specific salvage pathway of uridine metabolism for incorporation into viral RNA synthesis was not up-regulated in SARS2 infected tissues. Yet, 5-FU can be converted directly into uridine monophosphate (UMP) for incorporated into RNA. We therefore propose to use F-18 labeled pro-drug 5- fluorouracil (5-[18F]FU, the same molecule as 5-FU with isotopic substitution of F-19 by F-18) instead. Still, the rapid catabolism of 5-[18F]FU obscures interpretation of the PET images until the addition of eniluracil (5-ethynyluracil) that prevents the catabolism of 5-[18F]FU to obtain meaningful PET images of 5- [18F]FU uptake. Consequently, we propose to re-purpose 5-[18F]FU for PET imaging of SARS2 infection, and will use the same eniluracil to transiently maintain the integrity of 5-[18F]FU during the proposed PET imaging. We will test PET imaging with 5-[18F]FU using the readily available and clinically relevant model of mouse hepatitis virus (MHV) infection. MHV, a murine coronavirus very similar to SARS2 in structure, can cause a wide range of diseases in the mice and rats, including hepatitis, encephalomyelitis, enteritis, and, respiratory diseases. Many of these same organs were similarly affected during human SARS2 infection even though the acute lung injury related mortality symbolized COVID-19 in the public perception. Clinical utility of 5-[18F]FU PET imaging would be complementing PCR-based testing of COVID-19 (gold standard) or CT-based assessment (non-specific evaluation) of related lung disease. It could also be used to facilitate new anti-viral drug development (beyond remdesivir) for optimizing therapeutic dose and treatment duration, and for treatment monitoring in the future.

许多病毒通过利用宿主细胞提供的核苷酸进行复制来维持寄生生活方式。的由SARS-CoV-2（SARS 2）引起的2019冠状病毒病（COVID-19）的表现和进展，一种RNA病毒，伴随着病毒在受感染的宿主中利用宿主的机器进行扩增。的 SARS 2的快速扩增需要通过RNA合成的补救途径增加RNA合成，大多数特别是在非分裂细胞中，这些细胞是SARS 2感染的目标。这提供了一个机会如果可获得指示病毒RNA合成的成像示踪剂，则跟踪病毒感染的状态。与宿主相似，病毒相关的RNA合成（病毒基因组RNA或病毒信使RNA）发生在三个阶段：起始、延伸和终止。我们将重点关注病毒相关RNA的延伸合成，这是重复添加核苷一磷酸（NMP）的3'端的增长 RNA链。由于SARS 2需要大量的宿主细胞尿苷，其基因组的1/3是尿苷，尿苷是而且是亚基因组正链RNA合成/病毒功能所必需的。因此，放射性标记的应使用尿苷通过PET成像跟踪嘧啶代谢，以增强RNA合成， SARS 2感染。然而，掺入病毒RNA的尿苷代谢的特异性补救途径在SARS 2感染的组织中合成没有上调。然而，5-FU可以直接转化为尿苷单磷酸（UMP）用于掺入RNA。因此，我们建议使用F-18标记的前体药物5- 氟尿嘧啶（5-[18 F]FU，与5-FU相同的分子，F-19被F-18同位素取代）代替。尽管如此，5-[18F]FU的快速催化剂使PET图像的解释变得模糊，直到添加 eniluracil（5-乙炔基尿嘧啶），可防止5-[18 F]FU的催化作用，以获得有意义的5- [18F]FU摄取。因此，我们建议将5-[18F]FU重新用于SARS 2感染的PET成像，在拟定的PET成像期间，将使用相同的恩尿嘧啶暂时保持5-[18 F]FU的完整性。我们将使用现成的临床相关小鼠模型测试5-[18 F]FU的PET成像肝炎病毒（MHV）感染。MHV是一种在结构上与SARS 2非常相似的鼠冠状病毒，在小鼠和大鼠中广泛的疾病，包括肝炎、脑脊髓炎、肠炎和呼吸道疾病疾病在人类SARS 2感染期间，许多相同的器官受到类似的影响，急性肺损伤相关死亡率在公众认知中是COVID-19的象征。 5-[18F]FU PET成像的临床效用将补充基于PCR的COVID-19检测（黄金标准）或相关肺部疾病的基于CT的评估（非特异性评估）。它也可以用来促进新的抗病毒药物的开发（除了remdesivir），以优化治疗剂量和治疗持续时间，以及将来的治疗监测。