Host Polymorphisms and Uncomplicated Malaria

描述(申请人提供)：疟疾仍然是世界范围内最重要的传染病之一。通过对人类适应能力的影响，疟疾寄生虫对其宿主的遗传构成产生了重大影响。拟议的研究将检查在这种强烈的选择压力下出现的遗传变异性，并评估这种变异性对疟疾临床结果的影响。该项目的具体目标是：(1)评估宿主遗传多态对乌干达坎帕拉单纯疟疾发病率的影响；(2)评估宿主遗传多态对乌干达抗疟疾治疗反应的影响；(3)确定影响培养的疟疾寄生虫发展的宿主多态。为实现这些目标而设计的研究将利用分子技术来评估在乌干达进行的多项已完成和正在进行的抗疟疾药物疗效研究的受试者的多态。他们还将使用培养的疟疾寄生虫来评估人类红细胞多态的体外影响。这些研究的发现将有助于了解疟疾的发病机制。此外，识别针对这种寄生虫的自然宿主防御将有助于药物发现，并有助于药物和疫苗试验的设计。 申请者Sunil Parikh博士是一名传染病专家，对疟疾研究和国际卫生有着坚定的承诺。该项目旨在为他提供在转译临床疟疾研究、分子遗传学、流行病学和生物统计学方面的深入培训。指导将由在临床研究、分子寄生虫学和流行病学方面具有重叠专业知识的高级调查人员提供。有了这个项目获得的技能，帕里克博士将能够利用现代分子流行病学技术来研究疟疾易感性的人类遗传因素，他将为从事学术研究事业做好准备。

DESCRIPTION (provided by applicant): Malaria remains one of most significant infectious diseases world-wide. Through its impact on human fitness, the malaria parasite has had a substantial influence upon the genetic constitution of its host. The proposed research will examine the genetic variability which has arisen under this intense selective pressure and assess the impact of this variability on clinical malaria outcomes. The specific aims of this project are: (1) to assess the impact of host genetic polymorphisms on the incidence of uncomplicated malaria In Kampala, Uganda; (2) to assess the impact of host genetic polymorphisms on the response to antimalarial therapy in Uganda; (3) to identify host polymorphisms that impact upon the development of cultured malaria parasites. The studies designed to achieve these aims will utilize molecular techniques to evaluate polymorphisms in subjects from multiple completed and ongoing studies of antimalarial drug efficacy conducted in Uganda. They will also use cultured malaria parasites to evaluate the in vitro impacts of polymorphisms in human erythrocytes. Findings from these studies will contribute to the understanding of malaria pathogenesis. Additionally, the identification of natural host defenses against this parasite will aid in drug discovery, and assist in the design of drug and vaccine trials. The applicant, Dr. Sunil Parikh, is an infectious disease specialist with a strong commitment to malaria research and international health. This project is intended to provide him with in-depth training in translational clinical malaria research, molecular genetics, epidemiology, and biostatistics. Mentoring will be provided by senior investigators with overlapping expertise in clinical research, molecular parasitology, and epidemiology. With the skills gained from this project, Dr. Parikh will be able to utilize modern molecular epidemiology techniques to investigate human genetic factors underlying susceptibility to malaria and he will be well equipped for a career in academic research.