Functional genomic tools for in vivo study of P. vivax

用于间日疟原虫体内研究的功能基因组工具

• 批准号: 8089263
• 负责人: NICHOLAS Joseph SCHORK
• 金额: $ 28.2万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089263
• 关键词: Antigens; Antimalarials; Area; Back; Bioinformatics; Biological; Biology; Blood Cells; Chloroquine; Choking; Clinical; Copy Number Polymorphism; Data; Decision Making; Development; Disease; Dosage Compensation (Genetics); Drug Delivery Systems; Drug resistance; Enzymes; Erythrocytes; Exhibits; Foundations; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Genomics; Glucose-6-Phosphate; Immune; Immune system; In Vitro; Individual; Indonesia; Infection; Laboratories; Laboratory Study; Lead; Licensing; Linkage Disequilibrium; Liver; Malaria; Methods; Molecular; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Parasite resistance; Parasites; Patients; Pattern; Peru; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Plasmodium vivax; Plasmodium vivax vaccine; Population; Population Study; Primaquine; Primates; Reagent; Relapse; Reporting; Research Personnel; Research Project Grants; Resources; Salivary Glands; Sampling; Source; Specimen; Sporozoites; Staging; Structure; Testing; Toxic effect; Transfection; Vaccine Antigen; Vaccines; Variant; Vivax Malaria; Work; base; drug discovery; effective therapy; functional genomics; gene function; genome sequencing; in vivo; interest; neglect; next generation; novel; novel vaccines; pressure; prevent; response; tool; vaccine candidate; zygote

DESCRIPTION (provided by applicant): Efforts to eradicate malaria will depend on having effective therapies that can eliminate Plasmodium vivax. At present the only licensed antimalarial that can accomplish the elimination of the latent form of the parasite, the hypnozoites, is primaquine, which has liabilities in terms of likely widespread parasite resistance or tolerance, and toxicity to individuals with glucose 6 phosphate deficiency. There is also currently no licensed vaccine for P. vivax malaria. Efforts to study the mechanisms of drug resistance in P. vivax, to develop novel drugs or to discover new vaccine antigens are complicated by the fact that the parasite cannot be easily cultured, making it difficult to phenotype parasites, characterize genes or test hypotheses using molecular methods such as allelic exchange or transient transfection. Because of these difficulties genome-dependent methods offer one of the most efficient ways to determine what genes are doing, when they may be active in the parasite, how they are regulated, which genes may be interacting with the immune system, and which are under selective pressure from the host immune system or from drugs. As has been shown in P. falciparum descriptions of when genes are transcribed, and whether or not they are amplified or variable provides a foundation for a variety of drug and vaccine discovery research projects. For example copy number variants may be detected within the genome and genes whose activity levels are regulated by dosage compensation may prove to be interesting novel drug targets. Genes which are highly transcribed in the salivary gland sporozoite and which exhibit signatures of immune selection, such as CelTos, may encode new candidate antigens for preerythrocytic vaccines. This is an exploratory project that seeks to test the hypothesis that the same genome-dependent methods that have been used successfully with cultured P. falciparum can be used on P. vivax parasites that have been obtained directly from infected patients. If successful the work will establish a molecular toolbox that can be used by researchers working on field isolates of P. vivax and provide baseline transcription and variability data that may be useful to those making decisions about vaccine candidates, studying populations, relapse rates or the spread of drug resistance. The work will also provide reagents and bioinformatic resources that can be used by others studying P. vivax.

描述（由申请人提供）：根除疟疾的努力将取决于能够消除间日疟原虫的有效疗法。目前，唯一获得许可的能够消除潜伏形式的寄生虫（即催眠虫）的抗疟药是伯氨喹，它可能具有广泛的寄生虫抗性或耐受性，并且对葡萄糖6磷酸盐缺乏的个体具有毒性。目前也没有获得许可的间日疟原虫疟疾疫苗。研究间日疟原虫耐药性机制、开发新药或发现新疫苗抗原的努力因寄生虫不易培养的事实而复杂化，使得难以使用分子方法（如等位基因交换或瞬时转染）对寄生虫进行表型分析、表征基因或测试假设。由于这些困难，基因组依赖性方法提供了一种最有效的方法来确定基因在做什么，它们何时在寄生虫中活跃，它们如何被调节，哪些基因可能与免疫系统相互作用，以及哪些基因受到宿主免疫系统或药物的选择压力。如恶性疟原虫中所示，对基因何时转录以及它们是否扩增或可变的描述为各种药物和疫苗发现研究项目提供了基础。例如，可以在基因组中检测到拷贝数变异，并且其活性水平受剂量补偿调节的基因可以证明是令人感兴趣的新药物靶点。在唾液腺子孢子中高度转录并表现出免疫选择特征的基因，如CelTos，可能编码用于红细胞前疫苗的新候选抗原。这是一个探索性的项目，旨在验证以下假设：已成功用于培养恶性疟原虫的相同基因组依赖性方法可用于直接从感染患者中获得的间日疟原虫寄生虫。如果成功的话，这项工作将建立一个分子工具箱，可供研究间日疟原虫田间分离株的研究人员使用，并提供基线转录和变异性数据，这些数据可能对那些决定候选疫苗、研究人群、复发率或耐药性传播的人有用。这项工作还将提供试剂和生物信息学资源，可供其他研究间日疟原虫的人使用。