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Proteomics core

蛋白质组学核心

基本信息

批准号：
10512626
负责人：
Danielle L Swaney
金额：
$ 476.91万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512626
关键词：
ADP ribosylation Adenosine Diphosphate Ribose Antiviral Agents Binding Biological Biological Assay Biology COVID-19 Cell Culture Techniques Cell model Cells Cellular Assay Complex Cryoelectron Microscopy Data Detection Deuterium Development Disease Drug Interactions Drug Targeting Effectiveness Future Goals Healthcare Hospitals Hydrogen Immune response In Vitro Individual Infection Infrastructure Institutes Interferons Lead Mass Spectrum Analysis Measurement Measures Methodology Methods Modeling Molecular Monitor Nature Nonstructural Protein Oral Organism Outcome Peptide Hydrolases Pharmaceutical Preparations Pharmacotherapy Physiological Play Post-Translational Protein Processing Proteins Proteomics Recombinants Reproducibility Research Role Severity of illness Signal Transduction Specificity Structure System Technology Therapeutic Time Variant Vial device Viral Viral Physiology Viral Proteins Virus Work X-Ray Crystallography assay development base crosslink design drug candidate drug development drug discovery flexibility high risk in vivo in vivo Model interest multiplex assay novel pandemic disease polypeptide programs protein complex protein expression protein structure response screening small molecule stoichiometry structural biology success tool virology

项目摘要

CORE 8: PROTEOMICS SUMMARY Readily distributed, orally bioavailable small molecule antiviral agent could play an outsized role not only in the response to COVID-19, but also to future pandemics by reducing the severity of disease for those at highest risk for serious outcomes, and by curtailing the strain that serious illness puts on hospitals and healthcare infrastructure. Determining the molecular mechanism of biologically active viral proteins is a critical component to a successful drug development pipeline. Proteomics approaches represent a critical tool for the study of viral biology and drug development pipelines due to the capacity to assess viral protein activity in living cells using high-throughput multiplexed assays. Furthermore, the agnostic nature of protein detection allows for proteomics assays to be rapidly adapted to different viruses or host organisms. The work proposed by this core will be performed at the Thermo Fisher Scientific Proteomics Facility for Disease Target Discovery located at the J. David Gladstone Institutes at the UCSF campus. This facility and the Proteomics Core, will be led by Dr. Swaney, an expert in mass-spectrometry based proteomics research with a track record in the development and application of novel proteomics approaches to enable biological discovery. Within the QCRG Pandemic Response Program, the goal of the Proteomics Core is to provide high-quality, accurate, and reproducible proteomic analyses that measure viral proteins and their cellular activities. This will enable the QCRG Drug Discovery Platform to design and identify lead compounds and develop effective cell- based assays that measure drug candidate effectiveness in living cells. The proteomics assays described in this core are essential to the success of the QCRG Pandemic Response Program and will support all Projects, as well as the Screening Core, Integrative Modeling Core, and the In Vivo and In Vitro Virology Cores. Efforts of the Proteomics Core will include measuring the direct effect that drugs have on viral protein abundance and post-translational modifications during infection time courses in physiologically relevant cell models, and drug target specificity using cellular thermal shift assays. To aid flexible structure determination and viral protein assembly in cells and recombinant expression systems, we will also provide structural proteomics approaches to measure subunit stoichiometry, domain topology, and protein and drug interaction interfaces. Finally, we will develop assays to measure viral protein activity, including an ADP-ribosylation assay to measure macrodomain activity, and a protease cleavage assay to measure vial protease proteolytic activity.

核心8：蛋白质组学总结易于分布的、口服生物可利用的小分子抗病毒剂不仅可以在抗病毒治疗中发挥巨大作用，应对COVID-19，以及通过降低最高风险人群的疾病严重程度来应对未来的大流行病并通过减少严重疾病给医院和医疗保健带来的压力基础设施演进确定生物活性病毒蛋白的分子机制是一个关键组成部分一个成功的药物研发管道蛋白质组学方法是研究病毒感染的重要工具。生物学和药物开发管道，因为有能力评估活细胞中的病毒蛋白活性，高通量多重测定。此外，蛋白质检测的不可知性允许蛋白质组学检测方法可快速适应不同的病毒或宿主生物。该核心提出的工作将在Thermo Fisher Scientific Proteomics Facility for Disease 目标发现位于加州大学旧金山分校校园的J.大卫格莱斯顿研究所。这个设施和蛋白质组学核心将由Swaney博士领导，他是基于质谱的蛋白质组学研究专家，在开发和应用新的蛋白质组学方法以实现生物发现方面的记录。在QCRG大流行应对计划中，蛋白质组学核心的目标是提供高质量，准确和可重复的蛋白质组学分析，测量病毒蛋白及其细胞活性。这将使QCRG药物发现平台能够设计和识别先导化合物，并开发有效的细胞- 基于测定候选药物在活细胞中的有效性的测定。本文中描述的蛋白质组学测定法核心是QCRG流行病应对计划成功的关键，并将支持所有项目，以及筛选核心，综合建模核心，体内和体外病毒学核心。蛋白质组学核心的工作将包括测量药物对病毒蛋白的直接影响在生理相关细胞中感染时间过程中的丰度和翻译后修饰模型和使用细胞热位移测定的药物靶点特异性。为了帮助确定柔性结构，细胞和重组表达系统中的病毒蛋白质组装，我们还将提供结构蛋白质组学测量亚基化学计量、结构域拓扑以及蛋白质和药物相互作用界面的方法。最后，我们将开发检测病毒蛋白活性的方法，包括ADP-核糖基化检测，大结构域活性，和蛋白酶切割测定以测量小瓶蛋白酶蛋白水解活性。