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.

许多病毒通过利用核苷酸的宿主细胞供应进行复制来维持寄生的生活方式。这 Corona病毒疾病的表现和进展2019（COVID-19）是由SARS-COV-2（SARS2）引起的， RNA病毒伴随着使用宿主的机械在受感染宿主中的病毒膨胀。快速SARS2扩展需要通过RNA合成的挽救途径增强RNA合成，大多数特别是在非分散细胞中，这是SARS2感染的靶标。这提供了一个机会如果可以使用指示病毒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：启动，伸长和终止。我们将专注于病毒相关的RNA的伸长合成，这是在增长的3'末端重复添加核外侧单磷酸盐（NMP） RNA链。由于SARS2需要大量的宿主细胞尿苷，因此其1/3是尿苷，尿苷是此外，亚基因组阳性链RNA合成/病毒功能所需。彼此，放射性标签尿苷应用于通过PET成像以增强RNA合成在下的嘧啶代谢来追踪嘧啶的代谢。 SARS2感染。但是，尿苷代谢保险为病毒RNA的特定打捞途径在SARS2感染的组织中，合成没有上调。但是，5-FU可以直接转换为尿道单磷酸（UMP），用于掺入RNA中。因此，我们建议使用标记为Pro-Drug 5-的F-18 氟尿嘧啶（5- [18F] FU，与5-FU的分子相同，而F-19用同位素取代F-19）。尽管如此，5- [18f] fu的快速分解代谢掩盖了对宠物图像的解释，直到添加 Eniluracil（5-乙基拉氏菌）阻止了5- [18F] FU的分解代谢，以获得5--的有意义的PET图像 [18f] fu摄取。因此，我们建议将5- [18F] FU重新使用，以进行SARS2感染的PET成像，并且在提议的宠物成像过程中，将使用相同的依他拉氏菌瞬时保持5- [18F] FU的完整性。我们将使用鼠标随时可用和临床相关的模型使用5- [18F] FU测试PET成像肝炎病毒（MHV）感染。 MHV是一种与结构上非常相似的鼠冠状病毒，可能导致小鼠和大鼠的各种疾病，包括肝炎，脑脊髓炎，肠炎和呼吸道疾病。尽管急性肺损伤与死亡率相关的死亡率象征着Covid-19在公众的看法中。 5- [18F] FU PET成像的临床实用程序将是基于PCR的全面测试，即19 对相关肺部疾病的标准或基于CT的评估（非特异性评估）。它也可以习惯促进新的抗病毒药物开发（超越Remdesivir），以优化治疗剂量和治疗持续时间，以及未来的治疗监测。