Genetic determinants of Plasmodium vivax relapse

间日疟原虫复发的遗传决定因素

• 批准号: 8679282
• 负责人: Jessica Lin
• 金额: $ 16.89万
• 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/8679282
• 关键词: Adverse drug effect; Africa; Award; Bioinformatics; Bite; Blood Circulation; Clinical; Clinical Research; Clinical Trials; Commit; 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; Genomics; Genotype; Goals; High-Throughput Nucleotide Sequencing; Human; Infection; Investigation; Lead; Light; Liver; Malaria; Master of Science; Mentors; Methods; Metric; 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 variant; genome sequencing; genome wide association study; genome-wide; improved; next generation sequencing; professor; public health relevance; skills; therapeutic target; tool; transmission process

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，如果没有更好地了解非洲以外最普遍的疟疾物种，全球消除全球消除努力就无法成功。特别是，我们对维瓦克斯建立休眠性催眠阶段的能力的不良理解，该阶段重新激活以引起周期性复发，这是消除疟疾的主要障碍 可部署的抗释放疗法。该提案将使用新的基因组技术来更好地理解对维瓦克斯复发的遗传决定因素，其最终目标是确定治疗性干预的靶标。具体而言，鉴于Vivax的实验模型有限，我们将将下一代测序技术应用于来自Vivax感染的柬埔寨患者的临床样本，以对复发寄生虫的遗传特征进行首次详细介绍。在AIM 1中，我们将使用Amplicon深层测序来表征该队列中初始和复发性体内感染的宿主内多样性。结果将与微卫星基因分型，种群遗传分析和统计建模相结合，以区分复发与重新感染并确定易于复发的遗传变异。然后，我们将全基因组序列寄生虫在AIM 2中引起复发与非降低感染，以寻找与复发相关的遗传多态性。我们的总体假设是，经常复发的寄生虫包含孢子岩（ - 海运会前）特定基因的多态性，这些基因会增加催眠症的形成并赋予增加复发潜力。该候选人是北卡罗来纳大学传染病科的助理教授。她在东南亚拥有现场经验，在过去的5年中，在UNC的吉林斯全球公共卫生学院在疟疾中追求疟疾的临床和分子流行病学研究。拟议的调查将基于这个基础，使她在进行疟疾基因组学研究至关重要的基因组学，生物信息学，人群遗传学和遗传流行病学方面具有新的技能。她将借鉴导师在疟疾的下一代测序中的开创性努力，以及他们在疟疾流行病学，人群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动手讲习班，并完成临床研究硕士学位，其中包括临床研究设计的培训。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使用R01资金来进行基因组广泛的关联研究，并使用大型维瓦克斯队列进行复发。候选人的长期目标是成为一名领先的Vivax临床科学家，他将复杂的分子工具与临床研究相结合，以帮助消除疟疾。她的导师和她的部门在培养成功的医师科学家方面有着悠久的记录。他们致力于帮助她成为一名专门了解Vivax复发的遗传基础的转化调查员的独立性。