Translational Studies of Plasmodium Falciparum Infection Dynamics

描述(申请人提供)：这一K23奖项将为布莱恩·格林博士提供资源和保护时间，以实现以下职业发展目标：(1)成为疟疾流行病学和人口遗传学的独立翻译临床研究员；(2)开发先进的分子基因分型技术，研究疟疾寄生虫的传播；以及(3)应用流行病学、生物统计学和人口遗传学的先进原理，提高对抗药性疟疾的选择和传播的理解。为了实现这些目标，格林博士组建了一个指导团队，成员包括他的赞助人和主要导师菲利普·罗森塔尔博士，他在基础和转化疟疾研究方面拥有丰富的经验；以及两名共同导师：格兰特·多尔西博士，分子流行病学家，临床和转化疟疾研究的领导者，以及艾伦·哈伯德博士，他是生物统计学家，在传染病动态模型方面拥有先进的专业知识。培训将包括实验室研究、高级统计分析和获得生物统计学硕士学位的课程。 尽管近年来再次努力控制疟疾，但非洲部分地区的疟疾死亡率继续上升，这在很大程度上是由于耐药性的传播。由于对抗疟疾治疗对抗药性选择和传播的影响认识不足，限制了控制抗药性疟疾传播的努力的实施。在这个项目中，格林博士将研究恶性疟原虫的抗药性，利用一个由690名乌干达儿童组成的既定的、特征良好的队列，对其进行长达4.5年的跟踪调查，捕获所有疟疾病例，并对所有家庭进行GPS测绘。他将检验3个假设：1)用同样的疗法重复治疗疟疾会增加治疗失败的风险，并选择抗药性寄生虫；2)治疗失败的风险会随着时间的推移而增加，这种增加的风险可以用带有抗药性突变的寄生虫流行率的增加来解释；以及3)抗药性寄生虫的局部传播比敏感寄生虫的传播更有效。提出了三个具体目标：目标1：优化恶性疟原虫高分辨率基因分型技术；目标2：研究反复治疗疟疾对治疗结果和耐药突变选择的影响；以及目标3：研究乌干达一个特征良好的社区的耐药性传播情况。他将使用在目标1中开发的基因分型技术准确区分复发和新感染，描述最近的先前治疗和随后的治疗结果之间的关系，以及目标2中耐药突变的选择。在目标3中，他将评估治疗失败风险和寄生虫耐药突变流行率随时间的变化，并比较敏感和耐药寄生虫在队列中的相对传播情况。

DESCRIPTION (provided by applicant): This K23 award will provide Dr. Bryan Greenhouse with resources and protected time to achieve the following career development goals: (1) To become an independent translational clinical researcher in malaria epidemiology and population genetics; (2) To develop advanced molecular genotyping techniques to study the spread of malaria parasites; and (3) To apply advanced principles in epidemiology, biostatistics, and population genetics to improve understanding of selection and spread of drug-resistant malaria. To achieve these goals, Dr. Greenhouse has assembled a mentoring team comprised of his sponsor and primary mentor, Dr. Philip Rosenthal, who has extensive experience with basic and translational malaria research; and two co-mentors: Dr. Grant Dorsey, a molecular epidemiologist who is a leader in clinical and translational malaria research, and Dr. Alan Hubbard, a biostatistician with advanced expertise in dynamic models of infectious diseases. Training will entail laboratory research, advanced statistical analysis, and coursework resulting in a Master's degree in Biostatistics. Despite a renewal of efforts to control malaria in recent years, malarial mortality has continued to increase in parts of Africa due in large part to the spread of drug resistance. Implementation of efforts to control the spread of drug-resistant malaria are limited by a poor understanding of effects of antimalarial therapy on the selection and spread of drug resistance. In this project, Dr. Greenhouse will study P. falciparum drug resistance, taking advantage of an established, well-characterized cohort of 690 Ugandan children followed for 4.5 years, with capture of all malaria episodes and GPS-mapping of all households. He will test 3 hypotheses: 1) Repeated treatments for malaria with the same therapy increase the risk of treatment failure and select for drug-resistant parasites; 2) The risk of treatment failure will increase over time, and this increased risk can be explained by an increase in the prevalence of parasites with drug-resistance mutations; and 3) The local spread of resistant parasites is more efficient than that of sensitive parasites. Three specific aims are proposed: Aim 1: To optimize techniques for high-resolution genotyping of P. falciparum; Aim 2: To study the effect of repeated malaria treatment on the outcomes of therapy and selection of drug resistance mutations; and Aim 3: To study the spread of drug resistance in a well characterized community in Uganda. Using genotyping techniques developed in Aim 1 to accurately distinguish recrudescent from new infections, he will characterize the relationship between recent prior therapy and both subsequent treatment outcomes and the selection of drug resistance mutations in Aim 2. In Aim 3, he will assess changes in the risk of treatment failure and prevalence of drug-resistance mutations in parasites over time and compare the relative spread of sensitive and resistant parasites in the cohort.