Genetic diversity in virulence genes of Plasmodium falciparum

恶性疟原虫毒力基因的遗传多样性

基本信息

批准号：
8204845
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
项目类别：
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/8204845
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

项目摘要

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 DMA 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 PfEMPI, 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.

以下建议描述了一个为期五年的学术职业培训计划在传染病中。首席研究人员已经完成了她在内科的临床培训纽约长老会威尔·康奈尔医疗中心的耶鲁纽黑文医院和传染病。她现在旨在发展研究疟原虫分子生物学的研究技能恶性疟原虫具有建立独立研究计划的长期目标热带医学和分子生物学。首席研究人员已经开发了一项定制研究提案整合了DMA修复的分子生物学和热带医学研究。该建议将通过整合对疟疾的抗原变异的理解 DNA重组和修复的寄生虫机制以及场分离株的遗传分析。柯克博士 Deitsch将担任赞助商，并且是恶性疟原虫遗传操作的领导者。这个程序是威廉·霍洛曼（William Holloman）的共同赞助，他在DNA重组和维修方面的专业知识增强了增强了拟议的工作和主要研究人员的培训。研究将侧重于编码PFEMPI的VAR基因，这是与恶性假单胞菌的抗原变异。该表面蛋白还决定了感染红细胞，是恶性疟原虫感染中已知的毒力因子。临床样品的调查已显示该VAR基因在遗传上非常多样化。每个寄生虫分离物包含-60 var的补充独特的基因，因此给出了每个寄生虫的独特抗原分子库。如何产生的极端多样性尚未得到广泛的探索，是该研究建议的重点。转基因寄生虫线将用于直接研究DNA重组的不同机制在恶性疟原虫中维修。我们的转基因寄生虫线已经设计了，以便我们可以靶向DNA损伤用于对VAR基因编码区域或由VAR基因启动子驱动的药物选择标记物的维修分析。在这样，我们将能够研究DNA损伤和随后的维修如何有助于一代这个重要基因家族的多样性。对现场样本的VAR基因变化的研究将补充我们的从转基因寄生虫研究产生的数据。相关性：对在此关键寄生虫表面蛋白中产生多样性的机制的欣赏是了解恶性疟原虫感染的发病机理的基础。对宿主的进一步调查对疟疾感染的免疫反应以及寄生虫如何适应这种反应很重要指导干预措施，即疫苗和调查结果，减轻了全球疟疾的负担。