MicroCal PEAQ-DSC

基本信息

批准号：
10047566
负责人：
ANGELA M. GRONENBORN
金额：
$ 13.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2019-11-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047566
关键词：
Acquired Immunodeficiency Syndrome Administrative Supplement Binding Biochemical Biophysics Capsid Cell Surface Receptors Cells Complex Computer Analysis DNA Repair Disease Event Funding HIV HIV-1 Immunologic Factors Individual Infection Intervention Life Cycle Stages Membrane Fusion Nuclear Predisposition Process Production Proteins Proteomics Research Resolution Reverse Transcription Scanning Structure Time Viral Viral Genome Virus Virus Diseases Virus Integration fight against imaging study instrumentation new therapeutic target novel novel therapeutic intervention programs protein complex protein function success virology

Acquired Immunodeficiency Syndrome Administrative Supplement Binding Biochemical Biophysics Capsid Cell Surface Receptors Cells Complex Computer Analysis DNA Repair Disease Event Funding HIV HIV-1 Immunologic Factors Individual Infection Intervention Life Cycle Stages Membrane Fusion Nuclear Predisposition Process Production Proteins Proteomics Research Resolution Reverse Transcription Scanning Structure Time Viral Viral Genome Virus Virus Diseases Virus Integration fight against imaging study instrumentation new therapeutic target novel novel therapeutic intervention programs protein complex protein function success virology

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项目摘要

PCHPI Project Summary Essentially every step in the HIV life cycle interfaces intimately with the host cell machinery. The Pittsburgh Center of HIV Protein Interactions focuses on the steps and interactions that occur with the host after engagement of cell surface receptors and membrane fusion through integration of the viral genome into that of the host, the so called “early events”. Several essential molecular interactions and enzymatic activities occur within this time window, necessary for productive progression of the viral life cycle. Thus, it represents a pivotal period in the infection process, during which the susceptibility of the virus to disruptive interventions is likely to be high and little explored. Broadly speaking, the processes that we focus on include uncoating (the process by which the capsid disassembles), reverse transcription, evasion from innate immune factors, nuclear entry and integration. Given the importance of the capsid structure and its interactions for many of these processes, we also explore maturation and in particular formation of the capsid core. We are building on our successes and applying the extensive and complementary experimental expertise of our team to carry out 1) biochemical and high-resolution structure studies of individual proteins and complexes, 2) biochemical, biophysical, and proteomics analyses to identify novel interactions and complexes, 3) virology and imaging studies to understand protein function in the context of the cell and virus infection, and 4) computational analyses to elucidate the physical basis of capsid formation and capsid interactions with binding partners. Broadly, the program comprises projects on capsid interactions, the engagement of Vpr with the DNA repair machinery, and retroviral intasome structure. The requested administrative supplement will provide funds for the purchase of a differential scanning calorimeter, instrumentation essential for continued rigor in our protein production and characterization pipeline toward high-resolution structures of HIV-host protein complexes. Relevance Results provided by the proposed research are expected to have major implications in the global fight against AIDS, still considered an incurable disease with a pressing need for new therapeutic strategies and novel drug targets. Identifying and characterizing atomic structures of key HIV-1 host protein interactions in the immediate post-entry stage of the virus lifecycle will open new avenues in this endeavor.

PCHPI项目摘要本质上，HIV生命周期的每个步骤与宿主细胞机械紧密地接口。匹兹堡 HIV蛋白相互作用的中心侧重于与宿主发生的步骤和相互作用之后通过将病毒基因组整合到该基因组中的细胞表面受体和膜融合的参与主持人，所谓的“早期事件”。发生了几种必需的分子相互作用和酶活性在这个时间窗口中，对于病毒生命周期的生产效率所必需。那是一个代表感染过程中的关键时期，在此期间，病毒对干预措施的敏感性为可能很高，很少探索。从广义上讲，我们关注的过程包括无涂层（衣壳分解的过程），逆转录，先天免疫因子的进化，核进入和集成。鉴于衣壳结构的重要性及其相互作用对其中的许多过程，我们还探索了成熟，特别是CAPSID核心的形成。我们正在建立我们的成功并应用团队的广泛实验专家进行1）单个蛋白质和复合物的生化和高分辨率结构研究，2）生化，生物物理和蛋白质组学分析以识别新型相互作用和复合物，3）病毒学和成像在细胞和病毒感染的背景下了解蛋白质功能的研究，以及4）计算分析以阐明衣壳形成的物理基础和与结合伴侣的capsid相互作用。从广义上讲，该计划包括有关CAPSID互动的项目，VPR与DNA维修的参与机械和逆转录病毒的内压结构。请求的行政补品将为购买差异扫描量热仪，仪器对于我们蛋白质的持续严格必不可少的仪器生产和表征管道朝着HIV宿主蛋白复合物的高分辨率结构。关联拟议研究提供的结果预计将对全球斗争产生重大影响艾滋病仍然被认为是一种无法治愈的疾病，迫切需要新的治疗策略和新型药物目标。识别和表征关键HIV-1宿主蛋白相互作用的原子结构病毒生命周期的立即进入后阶段将在这项工作中开放新的途径。