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大了对疟疾发病机制的了解，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，从而能够利用分子模型为临床带来好处。由于寄生虫的进化和免疫力的变化，疟疾控制措施面临失败的风险，要维持在疟疾控制方面取得的成果，将需要以对疟疾发病机制的正确理解为基础的新一代疟疾治疗和预防措施。研究的重点是探索编码恶性疟原虫红细胞膜蛋白1(PfEMP1)的恶性疟原虫变种毒力基因家族。来自实验室和临床研究的一系列证据表明，PfEMP1是致病性和免疫原性的主要效应因子。由于寄生虫致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作用可以为改变宿主-寄生虫相互作用的平衡、降低发病率提供依据。这项提案中的项目试图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各种PfEMP1变异体，从而实现免疫逃逸并产生寄生虫致病表型；2)血红蛋白C对感染的天然抵抗力--它破坏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？以及3)严重疟疾状态下特定的PfEMP1转录本如何与寄生虫细胞黏附表型和适应性免疫反应的措施相关联？ 在短期内，这些项目旨在回答恶性疟原虫毒力的这些基本问题，并为初级研究人员培训微生物致病机制提供机会。候选人在临床医学、临床流行病学和分子流行病学方面拥有丰富的经验，并建议利用这些寄生虫毒力的研究作为过渡到疟疾发病机制职业生涯的一种手段。候选人将在一位在疟疾领域久负盛名并具有广泛专业知识的导师的指导下工作。调查将在吉林斯全球公共卫生学院的一个领先的流行病学系进行，为研究不同病原体的研究人员提供丰富的环境，跨越不同的学科，并在许多疟疾流行国家开展工作。拟议的研究将提供遗传分析方面的实践培训，并将辅之以寄生虫学、基因组流行病学和实验遗传学方面的更正式的研讨会和高级课程。在实验室之外，职业发展将通过两种机制得到加强：1)参加北卡罗来纳大学初级教员的正式研究规划研讨会，以帮助建立独立的研究计划；2)来自北卡罗来纳大学、杜克大学和NIAID的微生物发病机制和基因组学方面更资深的研究人员组成的科学咨询委员会的指导。临床批判性思维能力将通过与杜克大学签订的一项独特的合同安排来保持，这证明了两个独立机构对候选人职业成功的承诺。最终，研究独立将通过财务独立来建立，导师将致力于此。将利用两种途径获得外部支助：1)为来自吉林斯学院和北卡罗来纳大学的初级调查人员提供试点资金；2)利用拟议对各种实地和实验室R系列国家卫生研究院赠款申请进行的调查所产生的数据。 最终，这个K-08职业发展奖将产生一名翻译疟疾发病机制的独立研究员。实现这一目标的成功取决于1)候选人以前的培训和对学术研究的承诺，2)导师在疟疾遗传学和培训受训者方面的成功记录，3)对候选人及其跨学科环境的机构承诺，以及4)互补的职业发展机会和实验室调查，它们为疟疾毒力的翻译研究提供了一座桥梁。调查者和这一调查领域的长期目标是对疟疾发病机制形成更全面的理解，作为新的治疗方法、预防措施以及最终疫苗战略的基础。

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.