Translational Studies of Plasmodium Falciparum Infection Dynamics

本K23奖将为Bryan Greenhouse博士提供资源和保护时间，以实现以下职业发展目标：(1)成为一名独立的疟疾流行病学和种群遗传学转化临床研究人员；(2)发展先进的分子基因分型技术，研究疟原虫的传播；(3)运用流行病学、生物统计学和种群遗传学的先进原理，提高对耐药疟疾的选择和传播的认识。为了实现这些目标，Greenhouse博士组建了一个指导团队，其中包括他的赞助人和主要导师Philip Rosenthal博士，他在疟疾基础研究和转化研究方面拥有丰富的经验；以及两位共同导师：分子流行病学家格兰特·多尔西博士（Grant Dorsey）和生物统计学家艾伦·哈伯德博士（Alan Hubbard），前者是疟疾临床和转化研究领域的领军人物，后者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、高级统计分析和生物统计学硕士学位课程。

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.