Molecular pathogenesis and genetic diversification of childhood falciparum malari

描述（由申请人提供）：尽管最近在疟疾控制方面取得了进展，但恶性疟疾仍然是对全球健康的严重威胁。实地研究和实验室调查极大地扩展了对疟疾发病机制的理解，但这些发现尚未完全转化为对疟疾病理生理学的综合理解，从而可以利用分子模型为临床提供益处。由于疟疾控制措施由于寄生虫的进化和免疫力的变化而面临失败的风险，维持在疟疾控制方面取得的成果将需要基于对疟疾发病机制的正确理解的新一代治疗和预防疟疾措施。本研究的重点是探索编码恶性疟原虫红细胞膜蛋白1 （PfEMP1）的恶性疟原虫变异毒力基因家族。来自实验室和临床研究的证据表明，PfEMP1是致病性和免疫原性的主要效应因子。由于寄生虫发病机制和宿主免疫的相互作用导致疟疾临床发病率具有很大的异质性，因此更好地了解PfEMP1的进化机制及其在临床感染中的功能作用可以提供改变宿主-寄生虫相互作用平衡和降低发病率的方法。本项目旨在回答寄生虫发病机制的三个基本问题：1)恶性疟原虫群体如何产生不同的PfEMP1变异库，使免疫逃逸并产生寄生虫致病表型；2)血红蛋白C对感染的天然抗性——破坏PfEMP1的形态并在体外消除致病性——是否转化为临床感染中PfEMP1表达的中介？3)严重疟疾状态下特异性PfEMP1转录物如何与寄生虫细胞粘附表型和适应性免疫反应的测量相关联？

DESCRIPTION (provided by applicant): Falciparum malaria remains a grave threat to global health despite recent gains in malaria control. Field studies and laboratory investigations have greatly expanded the understanding of malaria pathogenesis, but these findings have not been fully translated into an integrated understanding of malaria pathophysiology that can leverage molecular models for clinical benefit. Because malaria control measures are at risk of failure due to parasite evolution and changes in immunity, sustaining the gains made in malaria control will require a new generation of therapeutic and preventive malaria measures that are based on a sound understanding of malaria pathogenesis. The focus of the proposed investigations is the exploration of the family of P. falciparum var virulence genes that encode the P. falciparum erythrocyte membrane protein 1 (PfEMP1). Lines of evidence drawn from both laboratory and clinical studies implicate PfEMP1 as a major effector of both pathogenicity and immunogenicity. Because the interaction of parasite pathogenesis and host immunity produces malaria clinical morbidity of great heterogeneity, a better understanding of the mechanisms of PfEMP1 evolution and its functional role in clinical infections can suggest means by which to alter the balance of the host-parasite interaction and reduce morbidity. The projects in this proposal seek to answer three basic questions of parasite pathogenesis: 1) How do P. falciparum populations generate diverse repertoires of PfEMP1 variants that enable immune escape and produce parasite pathogenic phenotypes?; 2) Does the natural resistance to infection conferred by hemoglobin C - which disrupts PfEMP1 morphology and abrogates pathogenicity in vitro - translate to a mediation of the expression of PfEMP1 in clinical infections?; and 3) How do specific PfEMP1 transcripts in severe malaria states correlate with measures of parasite cytoadherence phenotypes and adaptive immune response? In the short-term, these projects are intended to both answer these fundamental questions of P. falciparum virulence as well as provide opportunities for a junior investigator train in the investigation of microbial pathogenesi. The candidate has extensive experience with clinical medicine, clinical epidemiology, and molecular epidemiology, and proposes to use these investigations of parasite virulence as a means to transition to a career in malaria pathogenesis. The candidate will work under a mentor who is well-established in the malaria field and with a broad range of expertise. The investigations will be carried out in a leading epidemiology department in the Gillings School of Global Public Health, providing a rich environment of researchers working with diverse pathogens, across diverse disciplines, and in many malaria-endemic countries. The research proposed will provide hands-on training in genetic analyses that will be supplemented by more formal workshops and advanced courses in parasitology, genomic epidemiology, and experimental genetics. Career development will be augmented outside of the laboratory by two mechanisms: 1) participation in formal research planning seminars for junior faculty at UNC to assist in establishing independent research programs, and 2) guidance from a Scientific Advisory Committee of more senior investigators in microbial pathogenesis and genomics from UNC, Duke University, and NIAID. Clinical critical thinking skills will be maintained by a unique arrangement by contract with Duke, which testifies to the commitment to the candidate's career success from two independent institutions. Ultimately, research independence will be established by financial independence, and the mentor is committed to this. Two avenues of obtaining extramural support will be utilized: 1) pilot funding for junior investigators from both he Gillings School and UNC, and 2) leveraging the data generated in the proposed investigations into applications for a variety of field and laboratory-based R-series NIH grants. Ultimately, this K-08 career development award will produce an independent investigator in translational malaria pathogenesis. Success in achieving this goal is mediated by 1) the candidate's previous training and commitment to academic research, 2) the mentor's track record of success in malaria genetics and in training mentees, 3) the institutional commitment to the candidate and its cross-disciplinary environment, and 4) complementary career development opportunities and laboratory investigations that provide a bridge to translational studies of malaria virulence The long term goals of both the investigator and this field of investigation are to develop a more integrated understanding of malaria pathogenesis that can serve as a foundation for new therapeutics, preventive measures, and, ultimately, vaccine strategies.