Genetic determinants of Plasmodium vivax relapse

描述(申请人提供)：近年来，越来越多的人认识到，如果不更好地了解间日疟原虫，全球消除疟疾的努力就不可能成功，间日疟原虫是非洲以外最流行的疟疾物种。特别是，我们对间日疟原虫建立休眠催眠阶段的能力缺乏了解，这些阶段重新激活导致周期性复发是消除疟疾的主要障碍，因为缺乏 可部署的抗复发疗法。这项提案将使用新的基因组技术来更好地了解间日疟复发的遗传决定因素，最终目标是确定治疗干预的目标。具体地说，鉴于间日疟的实验模型有限，我们将对感染间日疟的柬埔寨患者的临床样本应用下一代测序技术，以首次详细了解复发寄生虫的遗传特征。在目标1中，我们将使用扩增子深度测序来表征该队列中初次和复发间日疟原虫感染的宿主内多样性。结果将与微卫星基因分型、群体遗传分析和统计建模相结合，以区分复发和再感染，并识别易复发的遗传变异。然后，我们将在目标2中对导致复发和非复发感染的寄生虫进行全基因组测序，以寻找与复发相关的遗传多态。我们的总体假设是，频繁复发的寄生虫含有子孢子(催眠体前)特异基因的多态，这种基因增加了催眠体的形成，并增加了复发的可能性。这位候选人是北卡罗来纳大学传染病系的助理教授。她在东南亚有现场经验，过去5年在北卡罗来纳大学吉林斯全球公共卫生学院从事疟疾临床和分子流行病学研究。拟议的研究将建立在这一基础上，使她掌握进行疟疾基因组学研究所必需的基因组学、生物信息学、人口遗传学和遗传流行病学方面的新技能。她将利用她的导师们在下一代疟疾测序方面的开创性努力，以及他们各自在疟疾流行病学、人口基因组学以及将这些学科应用于公共卫生方面的专业知识。该奖项还将为她提供受保护的时间，让她参加教学课程和实践研讨会，并完成临床研究理学硕士学位，其中包括临床研究设计培训。结合通过她的研究开发的初步数据和工具，这项培训将使她能够获得R01资金，利用大型间日疟队列进行全基因组范围的复发关联研究。这位候选人的长期目标是成为一名领先的间日疟临床科学家，将复杂的分子工具与临床研究相结合，帮助实现消除疟疾。她的导师和她所在的部门在培养成功的内科科学家方面有着长期的记录。他们致力于帮助她获得独立，成为一名致力于了解间日疟复发的遗传基础的翻译调查员。

DESCRIPTION (provided by applicant): In recent years, there has been an increased appreciation that global malaria elimination efforts cannot succeed without a better understanding of Plasmodium vivax, the most prevalent malaria species outside Africa. In particular, our poor understanding of P. vivax's ability to establish dormant hypnozoite stages that reactivate to cause periodic relapse is a major barrier to malaria elimination due to the lack of deployable anti-relapse therapy. This proposal will use new genomic technologies to achieve a better understanding of the genetic determinants of vivax relapse, with the ultimate goal of identifying targets for therapeutic intervention. Specifically, in light of limited experimental models of vivax, we will apply next generation sequencing techniques to clinical samples from vivax-infected Cambodian patients to provide the first detailed look at the genetic signatures of relapsing parasites. In Aim 1, we will use amplicon deep sequencing to characterize the in-host diversity of initial and recurrent vivax infections in this cohort. Results will be combined with microsatellite genotyping, population genetic analysis, and statistical modeling to distinguish relapses from re-infections and identify genetic variants predisposed to relapse. We will then whole genome sequence parasites causing relapsing vs. non-relapsing infection in Aim 2 to search for genetic polymorphisms associated with relapse. Our overall hypothesis is that frequently relapsing parasites contain polymorphisms in sporozoite (pre-hypnozoite) specific genes that increase hypnozoite formation and confer increased relapse potential. The candidate is an Assistant Professor in the Division of Infectious Diseases at the University of North Carolina. She has field experience in Southeast Asia, and has pursued clinical and molecular epidemiologic research in malaria for the past 5 years at UNC's Gillings School of Global Public Health. The proposed investigations will build on this foundation to equip her with new skills in genomics, bioinformatics, population genetics, and genetic epidemiology essential for conducting malaria genomics research. She will draw on her mentors' pioneering efforts in next generation sequencing of malaria as well as their respective expertise in malaria epidemiology, population genomics, and the application of these disciplines to public health. The Award will also provide protected time for her to attend didactic courses and hands-on workshops, and to finish a Master's of Science in Clinical Research that includes training in clinical study design. Combined with the preliminary data and tools developed via her research, this training will allow her to pursue R01 funding to conduct genome wide association studies of relapse using large vivax cohorts. The candidate's long-term goal is to become a leading vivax clinical scientist who combines sophisticated molecular tools with clinical studies to help achieve elimination of malaria. Her mentors and her division have a long track record in nurturing successful physician-scientists. They are committed to helping her achieve independence as a translational investigator devoted to understanding the genetic basis of vivax relapse.