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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：蛋白质组学摘要易于分布、口服生物可用的小分子抗病毒药物不仅在应对新冠肺炎，但也通过降低高危人群的疾病严重性来应对未来的大流行对于严重后果，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。确定具有生物活性的病毒蛋白的分子机制是一个关键组成部分一条成功的药物开发流水线。蛋白质组学方法是研究病毒的关键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路分析。此外，蛋白质检测的不可知性允许蛋白质组学快速适应不同病毒或宿主生物体的化验。该核心提议的工作将在Thermo Fisher疾病科学蛋白质组学设施进行目标发现号位于加州大学旧金山分校的J.大卫·格拉德斯通学院。这个设施和蛋白质组学核心将由斯万尼博士领导，他是一位基于质谱学的蛋白质组学研究专家在开发和应用新的蛋白质组方法以实现生物发现方面的跟踪记录。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、可重复的蛋白质组学分析，用于测量病毒蛋白质及其细胞活性。这将是使QCRG药物发现平台能够设计和鉴定先导化合物，并开发有效的细胞- 基于在活细胞中测量候选药物有效性的分析。其中描述的蛋白质组学分析核心对于QCRG流行病应对方案的成功至关重要，并将支持所有项目，如以及筛选核心、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质的直接影响生理相关细胞感染过程中的丰度和翻译后修饰模型，以及使用细胞热位移分析的药物靶标特异性。以帮助灵活的结构确定和病毒蛋白在细胞中的组装和重组表达系统，我们还将提供结构蛋白质组学亚基化学计量学、结构域拓扑以及蛋白质和药物相互作用界面的测量方法。最后，我们将开发检测病毒蛋白活性的方法，包括检测ADP-核糖化的方法。大域活性，以及测定小瓶蛋白水解酶活性的蛋白酶裂解试验。