Center for Structural Biology of HIV RNA

HIV RNA结构生物学中心

• 批准号: 10505786
• 负责人: ALICE TELESNITSKY
• 金额: $ 554.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-09 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505786
• 关键词: Address; Area; Biological; Biological Process; Biology; Cells; Chemistry; Complex; Cryoelectron Microscopy; Crystallization; Crystallography; Development; Disease; Electron Microscopy; Elements; Environment; Face; Gene Expression; Genetic Transcription; Goals; HIV; HIV-1; Host Defense; Image; Immune response; Immunologist; Infection; Integration Host Factors; Maintenance; Microscopy; Molecular; Optics; Play; Preparation; Prevention; Prevention approach; Process; Property; Proteins; Proviruses; RNA; RNA Splicing; RNA chemical synthesis; RNA metabolism; RNA-Protein Interaction; RNA-targeting therapy; Research Personnel; Resolution; Role; Sampling; Science; Services; Specialist; Structural Biologist; Structure; Technology; Therapeutic; Therapeutic Uses; Training; Translations; Viral; Viral Proteins; Virion; Virus Replication; base; biophysical techniques; clinically relevant; comparative; disorder prevention; drug discovery; genomic RNA; innovation; light microscopy; member; multidisciplinary; next generation; novel therapeutic intervention; particle; protein complex; protein function; reactivation from latency; structural biology; technology development; technology validation; therapeutic target; trafficking

This application for the Center for Structural Biology of HIV RNA (CRNA) focuses on determining the structural and mechanistic bases of HIV-1 RNA-related replication functions and the host’s response at the cellular, viral, and atomic levels. Although considerable progress has been made over the past 40 years in understanding how proteins function in HIV-1 replication, comparatively little is known about how HIV-1 RNA structures, dynamics, trafficking, and interactions with proteins alternately enable or limit virus replication. The past decade has provided transformative examples of the therapeutic use of RNA and RNA-targeted therapies, and recent progress by members of the proposed team has begun to unlock structural and dynamic features of RNA elements in HIV-1. Because HIV-1 RNA is exceptionally rich in biologic functions, the potential for RNA-targeted approaches in the prevention, maintenance, and cure of HIV-1 disease is highly compelling. However, this potential is limited by the general paucity of high-resolution structural information for RNA and protein-RNA complexes, which reflects inherent challenges in using RNA as a subject for structural analysis and the inadequacy of traditional biophysical approaches to address these challenges. The CRNA will face these challenges for HIV-1 RNA with its multidisciplinary team of structural biologists, chemists, cell and computational biologists, biochemists, immunologists, and virologists. Many are leaders in the study of HIV-1 RNA and the roles of its structures in virus replication, while others are new to the HIV-1 field and bring a fresh perspective and complementary expertise. Together, this team brings cutting edge technologies and incisive biologic approaches to overcome current technological obstacles, enabling mechanistic determination of the role of HIV- 1 RNA structures and associated proteins in viral transcription, splicing, translation, packaging, particle assembly, and interactions with host factors. These studies will enable the CRNA to advance goals of clinical relevance, including the development new RNA-centered strategies for treating HIV-1, the reactivation of latent proviruses as a potential approach for eradicating HIV-1 infection, and the augmentation of host defenses against HIV-1 infection. The proposed studies will also result in the development of powerful new computational, imaging, and structural biology technologies that can be applied to all areas of RNA biology.

HIV RNA (CRNA) 结构生物学中心的这项申请重点是确定 HIV RNA 的结构 HIV-1 RNA 相关复制功能的机制基础以及宿主对细胞、病毒、 和原子水平。尽管过去 40 年来在理解如何 蛋白质在 HIV-1 复制中发挥作用，但对于 HIV-1 RNA 的结构、动力学、 贩运以及与蛋白质的相互作用交替启用或限制病毒复制。过去十年已经 提供了 RNA 和 RNA 靶向疗法的治疗用途的变革性例子，以及最近 拟议团队成员的进展已开始解开 RNA 的结构和动态特征 HIV-1 中的元素。由于 HIV-1 RNA 具有异常丰富的生物学功能，因此 RNA 靶向治疗的潜力 预防、维持和治疗 HIV-1 疾病的方法非常引人注目。然而，这 RNA 和蛋白质-RNA 的高分辨率结构信息普遍缺乏，限制了其潜力 复合物，这反映了使用 RNA 作为结构分析对象和 传统的生物物理方法不足以应对这些挑战。 CRNA将面临这些 其由结构生物学家、化学家、细胞和计算学家组成的多学科团队应对 HIV-1 RNA 的挑战 生物学家、生物化学家、免疫学家和病毒学家。许多人都是 HIV-1 RNA 和 HIV-1 RNA 研究的领导者 其结构在病毒复制中的作用，而其他结构对于 HIV-1 领域来说是新的，并带来了新的视角 和互补的专业知识。该团队共同带来了尖端技术和深入的生物制剂 克服当前技术障碍的方法，能够机械地确定艾滋病毒的作用 1 病毒转录、剪接、翻译、包装、颗粒中的RNA结构和相关蛋白 组装以及与宿主因子的相互作用。这些研究将使 CRNA 能够推进临床目标 相关性，包括开发新的以 RNA 为中心的治疗 HIV-1 的策略、重新激活潜在的 原病毒作为根除 HIV-1 感染的潜在方法，并增强宿主对 HIV-1 的防御 HIV-1 感染。拟议的研究还将导致强大的新计算、成像、 以及可应用于RNA生物学所有领域的结构生物学技术。