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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.

下面的建议描述了一个五年的培训计划，以发展学术生涯传染病主要研究者已完成内科临床培训，耶鲁纽黑文医院和传染病在纽约长老会，威尔康奈尔医疗中心。她现在的目标是发展她的研究技能，研究疟原虫的分子生物学恶性疟原虫的长期目标是建立一个独立的研究计划，热带医学和分子生物学。首席研究员开发了一个定制的研究整合DMA修复的分子生物学和热带医学研究的建议。这一建议将进一步了解抗原变异的疟疾，结合研究的寄生虫的DNA重组和修复机制以及田间分离株的遗传分析。柯克博士 Deitsch将担任赞助商，是恶性疟原虫基因操作的领导者。这个程序是由威廉·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，加强主要调查员的拟议工作和培训。研究将集中在编码PfEMPI的var基因上，PfEMPI是与恶性疟原虫抗原变异。这种表面蛋白也决定了细胞粘附特性，感染的红细胞，恶性疟原虫感染中的一种已知毒力因子。临床样本调查显示变异基因在遗传上是极其多样的。每种寄生虫分离物含有-60 var的补体，这些基因是独特的，因此赋予每种寄生虫其独特的抗原分子库。这如何极端多样性的产生尚未得到广泛探索，这是本研究提案的重点。转基因寄生虫系将用于直接研究DNA重组的不同机制，恶性疟原虫的修复我们的转基因寄生虫系被设计成可以靶向DNA损伤用于对var基因编码区或由var基因启动子驱动的药物选择标记进行修复分析。在通过这种方式，我们将能够研究DNA损伤和随后的修复如何有助于产生这个重要基因家族的多样性。田间样品中var基因变化的研究将补充我们的转基因寄生虫的研究数据。相关性：了解这种关键寄生虫表面蛋白产生多样性的机制，了解恶性疟原虫感染的发病机制的基础。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能够适应这种反应是重要的，指导干预工作，即疫苗，并发现减少全球疟疾负担的方法。