Core 1 - Structural Biology Core

核心 1 - 结构生物学核心

• 批准号: 10506664
• 负责人: Priyamvada Acharya
• 金额: $ 89.03万
• 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/10506664
• 关键词: AIDS/HIV problem; B-Lymphocytes; Cells; Communities; Cryo-electron tomography; Cryoelectron Microscopy; Drug Design; Event; Evolution; Future; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Heterogeneity; Image Analysis; Immune system; Infection; Infrastructure; Kinetics; Light; Maps; Mediating; Methods; Mission; Modeling; Monitor; Persons; Preparation; Process; Protocols documentation; Research; Research Project Grants; Resolution; Roentgen Rays; Sampling; Series; Solid; Sorting - Cell Movement; Specimen; Structure; T-Cell Activation; Techniques; Technology; Temperature; Time; Tomogram; Vaccines; Viral; Virus; Virus Diseases; antiretroviral therapy; biological systems; computerized tools; cryogenics; env Gene Products; 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 全世界大约有 4000 万人感染了艾滋病毒/艾滋病，但是，保护性疫苗或功能性药物； 尽管经过四十年的深入研究，HIV-1 通过其免疫系统逃避，但治愈方法仍然难以实现。 杜克大学艾滋病病毒结构生物学中心将致力于研究感染和复制过程中的快速结构进化。 HIV-1 包膜 (Env) 蛋白进化的结构研究，以阐明结构功能机制 用于抗逆转录病毒治疗 ART 后的病毒进入、B 细胞和 T 细胞激活以及病毒反弹。 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总体使命 使用广泛的实验技术对 HIV-1 Env 进行结构分析将提供访问权限。 结构测定的尖端技术，具有强大的技术开发成分 这最终将促进我们对环境的机械理解。研究项目将受益于拥有。 访问已建立的结构测定协议以及该技术产生的新方法 结构生物学核心的具体目标是 1) 建立一个高 使用高通量管道对可溶性 HIV-1 三聚体的结构和动力学进行常规表征 分辨率单颗粒冷冻电镜；2) 开发用于天然 HIV-1 结构分析的先进工作流程 使用冷冻电子断层扫描 (ET) 以近原子分辨率对样品进行原位成像；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结构生物学的总体目标提供坚实的基础设施 中心及其组件提供最先进的结构测定技术。 以尽可能高的空间和时间分辨率检测 HIV-1，将为可视化提供独特的机会 可以帮助我们了解艾滋病病毒感染的关键中间体。 确定可溶性或天然形式的 Env 的高分辨率结构的能力对于提高我们的能力至关重要。 作为结构生物学核心的一部分开发的技术将产生影响。 超越艾滋病毒领域，并将有利于其他生物系统的结构研究。 对于结构生物学界来说，核心活动将产生更广泛的影响。