Molecular pathogenesis and genetic diversification of childhood falciparum malari

儿童恶性疟的分子发病机制和遗传多样性

• 批准号: 8660031
• 负责人: Steve Myer Taylor
• 金额: $ 12.36万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660031
• 关键词: Address; Advisory Committees; Africa South of the Sahara; Anemia; Antigens; Binding; Bioinformatics; Biological Assay; Blood; Case-Control Studies; Cerebral Malaria; Child; Childhood; Clinical; Clinical Medicine; Clinical Research; Collaborations; Commit; Complementarity Determining Regions; Contracts; Country; Critical Thinking; Data; Data Analyses; Developing Countries; Discipline; Disease; Educational workshop; Enrollment; Environment; Epidemiology; Equilibrium; Erythrocyte Membrane; Erythrocytes; Evolution; Experimental Designs; Experimental Genetics; Extramural Activities; Faculty; Failure; Falciparum Malaria; Family; Foundations; Functional disorder; Funding; Generations; Genes; Genetic; Genetic Recombination; Genomics; Genotype; Goals; Grant; Hemoglobin C; Heterogeneity; Humoral Immunities; Immune; Immune Sera; Immune response; Immunity; In Vitro; Individual; Infection; Institution; Intercellular adhesion molecule 1; Investigation; K-Series Research Career Programs; Laboratories; Laboratory Study; Ligands; Malaria; Measures; Mediating; Mediation; Membrane Proteins; Mentors; Modeling; Molecular; Molecular Epidemiology; Molecular Models; Morbidity - disease rate; Morphology; Mozambique; National Institute of Allergy and Infectious Disease; Natural Immunity; Natural Resistance; Parasitemia; Parasites; Parasitology; Pathogenesis; Pathogenicity; Patients; Pattern; Phenotype; Plasmodium falciparum; Plasmodium falciparum erythrocyte membrane protein 1; Population; Population Genetics; Preventive; Public Health; Recombinants; Research; Research Personnel; Resistance to infection; Resources; Risk; Role; Schools; Series; Severities; Specimen; Staging; Structure; Syndrome; Technology; Therapeutic; To specify; Training; Transcript; Translating; Translational Research; United States National Institutes of Health; Universities; Vaccines; Variant; Virulence; Virulence Factors; Work; asexual; base; career; career development; clinical epidemiology; experience; extracellular; field study; functional genomics; genetic analysis; global health; hemoglobin AA; immunogenic; immunogenicity; in vivo; investigator training; killings; microbial; molecular modeling; mortality; next generation sequencing; novel; novel therapeutics; novel vaccines; pathogen; prevent; programs; pyrosequencing; research study; skills; sound; success; translational study

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.

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获得临床益处。由于寄生虫的进化和免疫力的变化，疟疾控制措施有失败的风险，因此，要维持疟疾控制方面取得的成果，就需要在对疟疾发病机理有正确认识的基础上，采取新一代的治疗和预防疟疾措施。研究的重点是探索编码恶性疟原虫红细胞膜蛋白1（PfEMP 1）的恶性疟原虫变种毒力基因家族。从实验室和临床研究中得出的证据表明PfEMP 1是致病性和免疫原性的主要效应子。由于寄生虫发病机制和宿主免疫的相互作用产生了巨大异质性的疟疾临床发病率，因此更好地理解PfEMP 1进化机制及其在临床感染中的功能作用可以建议改变宿主-寄生虫相互作用平衡并降低发病率的方法。本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）恶性疟原虫种群如何产生不同的PfEMP 1变体库，使免疫逃逸和产生寄生虫致病表型？2)血红蛋白C在体外破坏PfEMP 1的形态并消除其致病性，它赋予的对感染的天然抵抗力是否转化为PfEMP 1在临床感染中表达的介导？和3）在严重疟疾状态下特异性PfEMP 1转录物如何与寄生虫细胞粘附表型和适应性免疫应答的测量相关？ 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，并为初级研究人员提供微生物病原体调查培训的机会。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，并建议将这些寄生虫毒力的调查作为过渡到疟疾发病机制职业生涯的一种手段。候选人将在一名在疟疾领域地位稳固并具有广泛专门知识的导师指导下工作。这些调查将在Gillings全球公共卫生学院领先的流行病学部门进行，为研究人员提供了一个丰富的环境，这些研究人员在许多疟疾流行国家从事不同病原体的研究，跨学科。拟议的研究将提供遗传分析方面的实践培训，并辅之以寄生虫学、基因组流行病学和实验遗传学方面的更正式的讲习班和高级课程。职业发展将通过两种机制在实验室外得到加强：1）参加正式的研究计划研讨会，为初级教师在斯坦福大学，以协助建立独立的研究计划，和2）从科学咨询委员会的指导更高级的研究人员在微生物发病机理和基因组学从斯坦福大学，杜克大学，和NIAID。临床批判性思维技能将通过与杜克的合同进行独特的安排，这证明了两个独立机构对候选人职业成功的承诺。最终，研究的独立性将建立在财务独立上，导师致力于此。获得校外支持的两种途径将被利用：1）从他吉林斯学校和麻省理工学院的初级研究员试点资金，和2）利用在拟议的调查中产生的数据到各种领域和实验室为基础的R系列NIH赠款的应用。 最终，这个K-08职业发展奖将产生一个翻译疟疾发病机制的独立调查员。能否成功实现这一目标取决于以下因素：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学员方面的成功记录，3）机构对候选人的承诺及其跨学科环境，和4）互补的职业发展机会和实验室研究，为疟疾毒力的转化研究提供桥梁研究者和这一研究领域的长期目标是对疟疾发病机理有更全面的了解，这可以作为新疗法、预防措施和最终疫苗战略的基础。