Genetic determinants of Plasmodium vivax relapse

间日疟原虫复发的遗传决定因素

• 批准号: 8991706
• 负责人: Jessica Lin
• 金额: $ 16.63万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991706
• 关键词: Adverse drug effect; Africa; Award; Bioinformatics; Bite; Blood Circulation; Cambodian; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Complement; Culicidae; Data; Detection; Discipline; Disease; Educational workshop; Epidemiologic Studies; Epidemiology; Exhibits; Experimental Models; Foundations; Frequencies; Funding; Future; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genomic Segment; Genomics; Genotype; Goals; Health; High-Throughput Nucleotide Sequencing; Human; Infection; Investigation; Lead; Light; Liver; Malaria; Master of Science; Mentors; Methods; Microsatellite Repeats; Minority; Molecular; Molecular Epidemiology; North Carolina; Parasites; Patients; Pattern; Persons; Physicians; Plasmodium vivax; Population; Population Genetics; Primaquine; Principal Component Analysis; Public Health; Recurrence; Regulator Genes; Relapse; Research; Research Design; Research Personnel; Research Training; Sampling; Schools; Scientist; Single Nucleotide Polymorphism; Southeastern Asia; Sporozoites; Staging; Statistical Models; Techniques; Technology; Therapeutic Intervention; Time; Training; Translating; Universities; Variant; Work; base; cohort; deep sequencing; design; drug relapse; experience; genetic analysis; genetic epidemiology; genetic signature; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic tools; improved; next generation sequencing; professor; relapse prediction; skills; targeted treatment; therapeutic target; tool; transmission process; whole genome

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.

描述（由申请人提供）：近年来，人们越来越认识到，如果不更好地了解非洲以外最流行的疟疾物种间日疟原虫，全球消除疟疾的努力就无法取得成功。特别是，我们对间日疟原虫建立休眠催眠子阶段并重新激活导致周期性复发的能力缺乏了解，这是消除疟疾的一个主要障碍， 可部署的抗复发治疗。该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。具体来说，鉴于间日疟原虫的实验模型有限，我们将对间日疟原虫感染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始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，以区分复发与再感染，并确定易复发的遗传变异。然后，我们将在目标2中对引起复发与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性。我们的总体假设是，经常复发的寄生虫含有子孢子（前催眠子）特异性基因的多态性，增加催眠子的形成，并赋予增加复发的可能性。候选人是北卡罗来纳州大学传染病系的助理教授。她有在东南亚的实地经验，并在过去的5年里一直从事疟疾的临床和分子流行病学研究，在墨尔本的Gillings全球公共卫生学院。拟议的调查将建立在这一基础上，使她具备进行疟疾基因组学研究所必需的基因组学、生物信息学、群体遗传学和遗传流行病学方面的新技能。她将利用她的导师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，人口基因组学以及这些学科在公共卫生中的应用方面的专业知识。该奖项还将为她提供受保护的时间参加教学课程和实践研讨会，并完成临床研究科学硕士学位，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，使用大型间日疟原虫队列进行复发的全基因组关联研究。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，以帮助实现消除疟疾。她的导师和她的部门在培养成功的物理学家和科学家方面有着悠久的历史。他们致力于帮助她实现独立，作为一个翻译研究人员致力于了解间日疟复发的遗传基础。