Higher-Order RNA Structure and Function in the HIV-1 Genome

 描述(申请人提供)：艾滋病毒/艾滋病流行仍然是一个重大的全球公共卫生挑战。目前有3500万人感染艾滋病毒，每年新增300万人。控制艾滋病毒感染的一个关键挑战是耐药毒株的进化。新的治疗策略对于有效地战胜病毒进化和消除艾滋病毒传播至关重要。目前的逆转录病毒疗法包括针对不同蛋白质功能的药物鸡尾酒；然而，病毒基因组RNA构成了病毒干预的未知靶点。病毒复制不仅取决于原始病毒中包含的遗传密码 序列，而且还研究了复杂的高阶RNA结构的功能作用。如果RNA结构要成为有效的治疗靶点，就必须开发RNA基因组中更高阶结构的准确、核苷酸分辨率模型。这项提议的目标是使用尖端的计算和实验方法来确定HIV-1基因组RNA中的功能基序。将制定计算策略，以识别和表征病毒成熟所必需的RNA-蛋白质相互作用，并对整个9,200个核苷酸的HIV-1基因组的三级结构基序进行建模。最终，这项研究将导致新的高通量结构建模策略，用于识别HIV-1内可应用于任何与疾病相关的RNA的新治疗靶点。通过这个培训计划，我将获得结构分析技术、下一代测序、生物信息学和病毒学方面的专业知识。我的长期目标是成为基于RNA的疾病研究的领导者，在我朝着这个目标努力的过程中，这一经历将是至关重要的。

 DESCRIPTION (provided by applicant): The HIV/AIDS epidemic remains a major global public health challenge. Currently 35 million individuals are infected with HIV, and 3 million new infections occur each year. A key challenge in controlling HIV infection is the evolution of drug-resistant strains. New therapeutic strategies are essential to effectively trump viral evolution an eliminate HIV spread. Current retroviral therapies consist of drug cocktails targeting diverse protein-based functions; however, the viral genomic RNA constitutes an unexplored target for viral intervention. Viral replication depends not only on the genetic code contained in the primary sequence, but also on the functional roles of complex high-order RNA structures. If RNA structure is to be an effective therapeutic target, accurate, nucleotide-resolution models of higher-order structures in the RNA genome must be developed. The goal of this proposal is to identify functional motifs in the HIV-1 genomic RNA using cutting-edge computational and experimental approaches. Computational strategies will be developed to identify and characterize RNA-protein interactions essential for viral maturation and to model tertiary structure motifs throughout the entire 9,200 nucleotide HIV-1 genome. Ultimately, this research will lead to novel high-throughput structural modeling strategies for identification of novel therapeutic targets within HIV-1 that can be applied to any disease-related RNA. Through this training program, I will gain expertise in structural analysis techniques, next generation sequencing, bioinformatics, and virology. My long-term goal is to become a leader in RNA-based disease research, and this experience will be critical as I work toward this objective.