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PET imaging of viral infection

病毒感染的 PET 成像

基本信息

批准号：
10285130
负责人：
Zhenghong Lee
金额：
$ 20.13万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285130
关键词：
2019-nCoV Acute Lung Injury Affect Antiviral Agents 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 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 base clinical application clinically relevant disease phenotype drug development 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的生活方式。的