Translational Studies of Plasmodium Falciparum Infection Dynamics

恶性疟原虫感染动力学的转化研究

• 批准号: 8110476
• 负责人: Bryan R Greenhouse
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110476
• 关键词: Africa; African; Antimalarials; Area; Behavior; Biometry; Child; Clinical; Clinical Data; Clinical Treatment; Combined Modality Therapy; Communicable Diseases; Communities; Country; Data; Data Analyses; Drug resistance; Educational process of instructing; Epidemiologist; Epidemiology; Equation; Fingerprint; Funding; Genetic; Genome; Genomics; Genotype; Goals; Grant; Household; Human; Individual; Infection; Laboratory Research; Learning; Logistic Regressions; Malaria; Maps; Master' s Degree; Measures; Mediator of activation protein; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; Methods; Microsatellite Repeats; Molecular; Molecular Genetics; Outcome; Parasite resistance; Parasites; Patients; Persons; Phenotype; Plasmodium falciparum; Policies; Population; Population Genetics; Population Study; Prevalence; Prior Therapy; Public Health; Randomized; Recrudescences; Regimen; Relative (related person); Research; Research Personnel; Resistance; Resolution; Resources; Risk; SNP genotyping; Statistical Methods; Structure; Study Subject; Techniques; Testing; Time; Training; Treatment Failure; Treatment Protocols; Treatment outcome; Uganda; career development; cohort; density; design; experience; follow-up; genetic analysis; genome wide association study; improved; infectious disease model; information gathering; longitudinal design; mortality; resistance mutation; response; therapy outcome; tool; translational study

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.

描述（由申请人提供）：该 K23 奖项将为 Bryan Greenhouse 博士提供资源和受保护的时间，以实现以下职业发展目标： (1) 成为疟疾流行病学和群体遗传学领域的独立转化临床研究员； (2) 开发先进的分子基因分型技术来研究疟疾寄生虫的传播； (3) 应用流行病学、生物统计学和群体遗传学方面的先进原理，提高对耐药疟疾选择和传播的认识。为了实现这些目标，Greenhouse 博士组建了一个指导团队，由他的赞助商和主要导师 Philip Rosenthal 博士组成，Philip Rosenthal 博士在基础和转化疟疾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 Grant Dorsey 博士，临床和转化疟疾研究领域的领导者；以及生物统计学家 Alan Hubbard 博士，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、高级统计分析以及获得生物统计学硕士学位的课程。 尽管近年来重新努力控制疟疾，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蔓延。由于对抗疟治疗对耐药性选择和传播的影响知之甚少，控制耐药性疟疾传播的努力的实施受到限制。在该项目中，Greenhouse 博士将研究恶性疟原虫耐药性，利用对 690 名乌干达儿童进行为期 4.5 年的既定、特征明确的队列跟踪，捕获所有疟疾发作并对所有家庭进行 GPS 绘图。他将测试3个假设：1）用相同的疗法重复治疗疟疾会增加治疗失败的风险并选择耐药寄生虫； 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耐药突变寄生虫患病率的增加来解释； 3) 抗药性寄生虫的局部传播比敏感寄生虫更有效。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：研究疟疾重复治疗对治疗结果和耐药突变选择的影响；目标 3：研究乌干达一个特征明确的社区中耐药性的传播情况。使用目标 1 中开发的基因分型技术来准确区分复发感染和新感染，他将描述近期先前治疗与后续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，他将评估随着时间的推移，治疗失败的风险和寄生虫耐药突变的患病率，并比较队列中敏感和耐药寄生虫的相对传播情况。