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The Expanded Repertoire of cGAMP Signal Transduction During Innate Immune Responses

先天免疫反应期间 cGAMP 信号转导的扩展库

基本信息

批准号：
10183204
负责人：
Shivam Zaver
金额：
$ 1.58万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-16 至 2021-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183204
关键词：
Address Amino Acids Antiviral Agents Autoimmune Diseases Bacteria Bacterial Infections Binding Binding Proteins Biochemical Biological Biological Assay Catabolism Cell Extracts Cell Proliferation Cell physiology Cells Cellular Metabolic Process Characteristics Chemicals Coupled Cyclic GMP Cytosol DNA DNA Viruses Development Dinucleoside Phosphates Disease Eukaryota Gene Activation Genes Glycolysis Hepatocyte Human Human Herpesvirus 8 Immune Immune response Immune signaling Immune system Immunity Immunocompetent In Vitro Infection Inflammation Inflammation Mediators Innate Immune Response Interferons Intervention Isoenzymes Lead Lytic Phase Maintenance Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metabolism Methods Modeling Molecular Morbidity - disease rate Nucleic Acids Nucleotides Nutritional Immunity Oncogenic Oncogenic Viruses Outcome Pentosephosphate Pathway Periodicity Phosphogluconate Dehydrogenase Play Process Production Prokaryotic Cells Proteins Proteomics Pyruvate Kinase Respiration Role Second Messenger Systems Shapes Signal Transduction Signaling Molecule Structure Tumor Immunity Viral Viral Proteins Virus Virus Diseases Virus Replication aerobic glycolysis analog autoimmune pathogenesis base cancer immunotherapy cell type combat cytokine enzyme activity fighting human disease immunoregulation metabolic abnormality assessment metaplastic cell transformation mortality novel novel therapeutic intervention novel therapeutics programs receptor response sensor transforming virus tumor tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Infections with oncogenic, DNA viruses account for twelve percent of human cancers and are a major cause of mortality and morbidity throughout the world. The development of new therapeutics to treat viral infections would significantly benefit from a detailed understanding of the host response to this infectious insult. The ability of the immune system to counteract viral infection is often mediated through a sophisticated repertoire of proteins that bind to viral nucleic acids. In response to DNA derived from viruses, the host protein cyclic GMP- AMP (cGAMP) Synthase (cGAS) produces the signaling nucleotide cGAMP, which initiates host inflammation to clear infection by binding to the protein Stimulatory of Interferon Genes (STING). However, second messenger signal transduction systems often rely on a variety of protein receptors to drive cellular responses. Whether cGAMP can function beyond STING activation to restrict viral infection and oncogenesis remains largely unknown. Recent studies have shown that cGAS and STING can have non-overlapping effects on infection outcome, suggesting that cGAS plays multiple roles in response to viral infection beyond signaling through STING. To systematically address this hypothesis, we have generated beads coated in cGAMP that are able to isolate cGAMP-binding proteins from cell extracts. Using this method, we have identified two new proteins other than STING that can bind to cGAMP. These novel cGAMP binding proteins have known roles in regulating cellular processes involved in the host response to infection including how the cell produces energy as well as biosynthetic building blocks, fundamental aspects of cellular physiology that viruses rely upon in order to facilitate replication. Here, I propose to utilize structure-function analysis coupled with biochemical and infection models to interrogate the biological relevance of these previously unrecognized cGAMP-binding proteins and detail their effects on viral restriction. The findings from these studies will significantly inform the mechanisms by which the host immune system can restrict viral infection and oncogenesis and may provide new therapeutic strategies to combat infectious and malignant diseases.

项目总结/文摘