Genetic diversity in virulence genes of Plasmodium falciparum

恶性疟原虫毒力基因的遗传多样性

• 批准号: 8004965
• 负责人: Laura Kirkman
• 金额: $ 13.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004965
• 关键词: Address; Antibody Formation; Antigenic Variation; Antigens; Area; Biological; Blood capillaries; Cells; Cerebrum; Cessation of life; Clinical; Code; Communicable Diseases; Complement; DNA; DNA Damage; DNA Repair; Data; Data Analyses; Disease Outbreaks; Double Strand Break Repair; Environment; Erythrocytes; Event; Family; Gene Conversion; Gene Family; Gene Rearrangement; Generations; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genotype; Goals; Hospitals; Human; Immune response; Immune system; Individual; Infection; Internal Medicine; Intervention; Investigation; Malaria; Medical center; Membrane Proteins; Molecular; Molecular Biology; New York; Organ; Organism; Parasites; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Play; Presbyterian Church; Principal Investigator; Process; Program Development; Property; Proteins; Research; Research Personnel; Research Proposals; Role; Sampling; Site; Sorting - Cell Movement; Staging; Surface Antigens; Surveys; Syndrome; Testing; Time; Training; Training Programs; Transgenic Organisms; Tropical Medicine; Vaccines; Variant; Virulence; Virulence Factors; Work; capillary; career; design; genetic analysis; genetic manipulation; in vivo; pathogen; programs; promoter; repaired; response; skills; vaccine development

DESCRIPTION (provided by applicant): The following proposal describes a five-year training program for the development of an academic career in Infectious Diseases. The principal investigator has completed her clinical training in Internal Medicine at Yale New Haven Hospital and Infectious Diseases at New York Presbyterian, Weill Cornell Medical Center. She now aims to develop her research skills studying the molecular biology of the malaria parasite Plasmodium falciparum with the long term goal of establishing an independent research program combining tropical medicine and molecular biology. The principal investigator has developed a customized research proposal integrating molecular biology of DNA repair and the study of tropical medicine. This proposal will further the understanding of antigenic variation in malaria by integrating the study of the parasite mechanisms for DNA recombination and repair and the genetic analysis of field isolates. Dr. Kirk Deitsch will serve as sponsor and is a leader in the genetic manipulations of P. falciparum. This program is enhanced by the co-sponsorship of Dr. William Holloman, his expertise in DNA recombination and repair enhances both the proposed work and the training of the principal investigator. Research will focus on the var genes that encode PfEMP1, the primary surface protein implicated in antigenic variation of P. falciparum. This surface protein also determines the cytoadherent properties of an infected red cell, a known virulence factor in P. falciparum infection. Surveys of clinical samples have shown that var genes are extremely diverse genetically. Each parasite isolate contains a complement of -60 var genes that is unique, thus giving each parasite its own distinct repertoire of antigenic molecules. How this extreme diversity is generated has not been extensively explored and is the focus of this research proposal. Transgenic parasite lines will be used to directly study different mechanisms of DNA recombination and repair in P. falciparum. Our transgenic parasite lines have been designed so that we can target DNA damage for repair analysis to var gene coding regions or drug selectable markers driven by var gene promoters. In this way, we will be able to study how DNA damage and subsequent repair may contribute to the generation of diversity in this important gene family. The study of var gene changes in field samples will complement our data generated from the study of transgenic parasites. Relevance: Appreciation of the mechanisms that generates diversity in this key parasite surface protein is fundamental to understanding the pathogenesis of P. falciparum infections. Further investigation of the host immune response to malaria infection and how the parasite is able to adapt to this response is important in directing intervention efforts, ie vaccines, and findings ways reduce the burden of malaria worldwide.

描述(由申请者提供)：以下建议描述了一项为期五年的传染病学术生涯发展培训计划。这位首席研究员已经在耶鲁大学纽黑文医院完成了内科临床培训，并在纽约长老会威尔康奈尔医学中心完成了传染病专业的培训。她现在的目标是发展自己的研究技能，研究疟疾寄生虫恶性疟原虫的分子生物学，长期目标是建立一个结合热带医学和分子生物学的独立研究项目。首席研究员制定了一项定制的研究计划，将DNA修复的分子生物学和热带医学研究结合在一起。 这一建议将通过整合DNA重组和修复寄生虫机制的研究以及野外分离株的遗传分析来加深对疟疾抗原变异的理解。柯克·德奇博士将担任赞助商，他是恶性疟原虫基因操作方面的领导者。这一计划得到了威廉·霍洛曼博士的共同赞助，他在DNA重组和修复方面的专业知识加强了拟议的工作和首席研究员的培训。 研究将集中在编码PfEMP1的var基因上，PfEMP1是与恶性疟原虫抗原变异有关的主要表面蛋白。这种表面蛋白还决定了受感染红细胞的细胞黏附特性，这是恶性疟原虫感染的已知毒力因素。对临床样本的调查表明，var基因在遗传上极其多样化。每个寄生虫分离株都包含一个独特的-60个var基因，因此每个寄生虫都有自己独特的抗原分子谱系。这种极端的多样性是如何产生的，还没有得到广泛的探索，这是本研究提案的重点。转基因寄生虫系将被用来直接研究恶性疟原虫不同的DNA重组和修复机制。我们的转基因寄生虫系已经设计成可以针对DNA损伤进行修复分析，以修复由var基因启动子驱动的var基因编码区或药物选择标记。通过这种方式，我们将能够研究DNA损伤和随后的修复可能如何有助于这个重要基因家族的多样性的产生。对田间样本中var基因变化的研究将补充我们从转基因寄生虫研究中产生的数据。 相关性：对这种关键寄生虫表面蛋白产生多样性的机制的认识是理解恶性疟原虫感染发病机制的基础。进一步研究宿主对疟疾感染的免疫反应，以及寄生虫如何能够适应这种反应，对于指导干预工作，即疫苗和研究结果，对于减少全球疟疾负担具有重要意义。