Core 1 - Structural Biology Core

核心 1 - 结构生物学核心

• 批准号: 10643911
• 负责人: Priyamvada Acharya
• 金额: $ 111.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-14 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643911
• 关键词: B-Lymphocytes; Communities; Cryo-electron tomography; Cryoelectron Microscopy; Drug Design; Event; Evolution; Future; Goals; HIV; HIV Envelope Protein gp120; HIV-1; HIV/AIDS; Heterogeneity; Image Analysis; Immune Evasion; Immune system; Infection; Infrastructure; Kinetics; Light; Maps; Mediating; Methods; Mission; Modeling; Monitor; Persons; Preparation; Process; Proteins; Protocols documentation; Research; Research Project Grants; Resolution; Roentgen Rays; Sampling; Series; Solid; Sorting; Specimen; Structure; T-Cell Activation; Techniques; Technology; Temperature; Time; Vaccines; Viral; Virus; Virus Diseases; Visualization; antiretroviral therapy; biological systems; computerized tools; cryogenics; expectation; improved; in situ imaging; millisecond; movie; particle; structural biology; technology development; temperature jump; temporal measurement; tool; viral rebound

Abstract – Core 1 – Structural Biology Core Approximately 40 million people worldwide are living with HIV/AIDS; however, a protective vaccine or functional cure remain elusive despite four decades of intense research. HIV-1 evades the immune system through its rapid structural evolution during infection and replication. The Duke Center for HIV Structural Biology will pursue structural studies of the evolution of the HIV-1 Envelope (Env) protein to elucidate structure-function mechanisms for viral entry, B-cell and T-cell activation, and viral rebound after antiretroviral therapy ART. The Structural Biology Core (Core 1) will support the overall mission of the Center by establishing a state-of-the-art pipeline for structural analysis of HIV-1 Env using a wide range of experimental techniques. The Core will provide access to cutting-edge techniques for structure determination and have a strong component of technology development that will ultimately advance our mechanistic understanding of Env. The research projects will benefit from having access to established protocols for structure determination as well as new methods resulting from the technology development efforts of the core. The Specific Aims of the Structural Biology Core are 1) to establish a high- throughput pipeline for routine characterization of the structure and dynamics of soluble HIV-1 trimers using high- resolution single-particle cryo-EM; 2) to develop advanced workflows for structural analysis of native HIV-1 samples imaged in-situ using cryo-electron tomography (ET) at near-atomic resolution; and 3) to establish structural methods for microsecond time resolution structural studies of HIV-1 Env. Completion of the three proposed aims will provide a solid infrastructure in structural biology needed to support the overall goals of the Center and its components. By providing access to state-of-the-art technology for the determination of structures of HIV-1 at the highest possible spatial and temporal resolution, will provide unique opportunities for visualizing key intermediates that could inform our understanding of HIV viral infection. The ability to determine high-resolution structures of soluble or native forms of Env will be critical to improve our understanding of HIV. The technologies developed as part of the Structural Biology Core will have implications beyond the field of HIV and would benefit structural studies of other biological systems. By making our tools available to the structural biology community, the activities of the core will have an even wider impact.

摘要 - 核心1 - 结构生物学核心 全世界约有4000万人患有艾滋病毒/艾滋病；但是，受保护的疫苗或功能 治愈仍然是难以捉摸的任务四十年的深入研究。 HIV-1通过其逃避免疫系统 感染和复制过程中的快速结构演变。杜克大学艾滋病毒结构生物学中心将追求 HIV-1包膜（ENV）蛋白演化以阐明结构功能机理的结构研究 对于病毒输入，B细胞和T细胞激活以及抗逆转录病毒疗法后的病毒反弹。结构 生物学核心（核心1）将通过建立最先进的管道来支持该中心的整体任务 使用广泛的实验技术对HIV-1 ENV进行结构分析。核心将提供对 用于结构确定的尖端技术，并具有很强的技术开发组成部分 这最终将提高我们对Env的机械理解。研究项目将受益于 访问已建立的协议进行结构确定以及技术产生的新方法 核心的发展工作。结构生物学核心的具体目的是1）建立高 吞吐量管道，用于使用高级固体HIV-1三聚体结构和动力学的常规表征 分辨率单粒子冷冻EM； 2）开发用于天然HIV-1结构分析的高级工作流程 使用低原子分辨率的冷冻电子层析成像（ET）成像的样品； 3）建立 HIV-1 Env的微秒时间分辨率结构研究的结构方法。完成三个 拟议的目标将为支持支持的整体目标提供稳固的基础设施 中心及其组件。通过提供最先进的技术来确定结构 HIV-1的最高空间和临时分辨率，将为可视化提供独特的机会 主要中间体可以告知我们对HIV病毒感染的理解。 确定固体或原生env的高分辨率结构的能力对于改善我们的 对艾滋病毒的理解。作为结构生物学核心的一部分而开发的技术将有含义 除了艾滋病毒领域，还将受益于其他生物系统的结构研究。通过制造我们的工具 可用于结构生物学社区，核心的活动将产生更广泛的影响。