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人口遗传学的独立转化临床研究人员； （2）开发高级分子基因分型技术来研究疟原虫的传播； （3）在流行病学，生物统计学和人群遗传学中​​应用高级原则，以提高对耐药疟疾的选择和传播的理解。为了实现这些目标，Greenhouse博士组建了一个由他的赞助商和主要导师Philip Rosenthal博士组成的指导团队，他在基本和转化的疟疾研究方面拥有丰富的经验。和两个联合给出者：分子流行病学家格兰特·多尔西（Grant Dorsey）博士是临床和转化疟疾研究的领导者，以及在传染病动态模型中具有先进专业知识的生物统计学家艾伦·哈伯德（Alan Hubbard）博士。培训将需要实验室研究，高级统计分析和课程工作，从而获得生物统计学的硕士学位。 尽管近年来为控制疟疾的努力做出了更新，但由于耐药性的传播很大程度上，非洲部分地区的疟疾死亡率仍在继续增加。对控制抗药性疟疾传播的努力的实施受到对抗疟疾治疗对耐药性选择和传播影响的影响的不良理解的限制。在该项目中，Greenhouse博士将利用既定，富有特征的乌干达儿童的既定，特征良好的队列进行了4。5年，并捕获了所有疟疾发作和所有家庭的GPS映射。他将检验3个假设：1）对疟疾进行相同疗法的重复治疗增加了治疗衰竭的风险，并选择抗药性寄生虫； 2）随着时间的推移，治疗失败的风险将增加，并且这种增加的风险可以通过抗药性突变的寄生虫患病率的增加来解释； 3）抗性寄生虫的局部扩散比敏感寄生虫的效率更有效。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的技术；目的2：研究反复疟疾治疗对治疗结果和耐药性突变的选择的影响；目标3：研究抗药性在乌干达一个有特征的社区中的传播。使用AIM 1中开发的基因分型技术来准确区分新感染和新感染，他将表征最近先前的治疗与随后的治疗结果与AIM 2中的耐药性突变选择之间的关系。在AIM 3中，他将评估parasites and Parasites Over partiste and companter and semant semant semant semant semhers semhers semhers semhers sefers sef semhers semhers sefers semhers semhers sefers semhers sefers sef semhers semhers semhers semhers sefers sef的变化。