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）：消除疟疾的努力将取决于具有可以消除疟原虫的有效疗法。目前，唯一可以消除寄生虫的潜在形式的抗疟药是催眠剂，是primaquine，其在可能广泛的寄生虫耐药性或耐受性方面具有责任，并且对患有葡萄糖6磷酸6磷酸盐缺乏症的个体具有毒性。目前还没有用于疟原虫疟疾的许可疫苗。研究寄生虫不能轻易培养，使寄生虫不容易培养，从而使表型寄生虫，表征基因或使用分子方法（例如ASELELIC EXPRANIT或瞬时转染）难以表征基因或测试假设，从而使研究耐药药的机制，开发新药物或发现新的疫苗抗原的努力变得复杂。由于这些困难，基因组依赖性方法提供了确定基因在做什么的最有效方法之一，何时可能活跃在寄生虫中，它们的调节方式，哪些基因可能与免疫系统相互作用，哪些基因可能在宿主免疫系统或药物中选择性压力。如恶性疟原虫的描述所示，何时转录基因，以及它们是否被放大或变量为各种药物和疫苗发现研究项目提供了基础。例如，可以在基因组和活性水平受剂量补偿调节的基因中检测到拷贝数变异，这可能被证明是有趣的新型药物靶标。在唾液腺孢子岩中高度转录并表现出免疫选择的特征的基因（例如凯尔特斯）可能会用新的候选抗原编码用于前疫苗前疫苗的新候选抗原。这是一个探索性项目，试图检验以下假设：与培养的恶性疟原虫成功使用的相同基因组依赖性方法可以用于直接从感染患者那里获得的静脉寄生虫。如果成功的话，该工作将建立一个分子工具箱，该工具箱可以由在拟南芥的现场分离株中使用，并提供基线转录和可变性数据，这些数据可能对那些对候选疫苗的决策，研究人群，复发率或耐药性的扩散可能有用。这项工作还将提供其他研究P. vivax可以使用的试剂和生物信息学资源。