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.

这项申请适用于结构生物学中心的HIV RNA(CRNA)，重点是确定其结构 以及HIV-1RNA相关复制功能和宿主在细胞、病毒、 和原子水平。尽管在过去的40年里，在理解如何 蛋白质在HIV-1复制中的作用，人们对HIV-1RNA的结构，动态， 贩运和与蛋白质的相互作用交替地启用或限制病毒复制。在过去的十年里 提供了RNA和RNA靶向疗法的治疗应用的变革性例子，以及最近 拟议团队成员的进展已经开始揭开RNA的结构和动态特征 HIV-1病毒中的成分。由于HIV-1RNA具有异常丰富的生物功能，因此以RNA为靶标的潜力 预防、维护和治愈艾滋病毒-1疾病的方法非常有说服力。不过，这个 核糖核酸和蛋白质-核糖核酸的高分辨率结构信息的普遍缺乏限制了潜力。 复合体，这反映了使用RNA作为结构分析的主题的内在挑战，以及 传统生物物理方法不足以应对这些挑战。中国核糖核酸将面对这些 HIV-1RNA及其结构生物学家、化学家、细胞和计算多学科团队面临的挑战 生物学家、生物化学家、免疫学家和病毒学家。许多人是研究艾滋病毒-1RNA和 它的结构在病毒复制中的作用，而其他结构对HIV-1领域是新的，并带来了新的视角 和互补的专业知识。这个团队共同带来了尖端技术和精辟的生物 克服目前技术障碍的方法，能够机械性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结构和相关蛋白质 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，包括为治疗艾滋病毒-1制定以RNA为中心的新战略，重新激活潜伏病毒 前病毒是根除HIV-1感染和增强宿主防御能力的潜在方法 HIV-1感染。拟议的研究还将导致开发强大的新计算、成像、 以及可应用于RNA生物学所有领域的结构生物学技术。