var gene regulation mechanisms in Malaria parasite Plasmodium falciparum

疟原虫恶性疟原虫var基因调控机制

• 批准号: 9025564
• 负责人: Lubin Jiang
• 金额: $ 12.97万
• 依托单位: INSTITUT PASTEUR OF SHANGHAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025564
• 关键词: Affect; Antibodies; Antibody Response; Antigenic Variation; Antimalarials; Binding; Bioinformatics; Biological Assay; Blood; Cell Nucleus; Cerebral Malaria; Chromatin; Chromatin Interaction Analysis by Paired-End Tag Sequencing; Chromosome Positioning; Complex; Coupled; Development; Electrophoretic Mobility Shift Assay; Epigenetic Process; Erythrocyte Membrane; Erythrocytes; Event; Family; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Transcription; Genome; Goals; Health; Histone H3; Histones; Human; Immune; Immune response; Immunoprecipitation; In Vitro; Infection; Knock-out; Knowledge; Label; Lead; Lysine; Malaria; Mediating; Membrane Proteins; Metabolic; Molecular; Nuclear Extract; Organ; Parasites; Pathogenesis; Pattern; Phase; Plasmodium; Plasmodium falciparum; Proteins; RNA; RNA-Binding Proteins; Regulation; Regulator Genes; Resources; Rest; Role; SET Domain; Spleen; Staging; Surface; Untranslated RNA; Vaccines; Virulence; Virulence Factors; asexual; base; design; enhancer-binding protein AP-2; genetic manipulation; genetic variant; histone methyltransferase; histone modification; improved; killings; malaria infection; member; new therapeutic target; next generation sequencing; novel; parasite genome; placental malaria; prevent; promoter; protein complex; receptor; success; tandem mass spectrometry; tool

 DESCRIPTION (provided by applicant): With improved financial and technical supports, many malaria endemic nations are once again considering malaria elimination as their national goal of malaria control. To achieve this ambitious goal, one of the greatest challenges is development of blood stage vaccines. Antigenic variation of PfEMP1 encoded by a 60-member var gene family and clonally expressed on the surface of Plasmodium falciparum-infected red blood cells is a critical virulence factor for malaria. Despite its central role in malaria pathogenesis during the asexual blood stage, the mechanism of mutually exclusive expression of var genes is still poorly understood, and this knowledge gap severely hinders the development of novel tools to kill blood stage parasites. This project, built on our recent success in creating a P. falciparum line with expression of all the var genes, aims to determine the molecular regulatory network and establish the hierarchy of var gene regulation mechanisms employing a set of recently developed genetic and epigenetic tools and resources. A comprehensive picture of var gene regulatory factors generated from this study will enable a better understanding of antigenic variation of the var gene family in immune evasion of malaria parasites. This information will also provide new targets for therapeutics to block PfEMP1-mediated immune evasion or complications of severe malaria, or enhance the ability of vaccines to maximize PfEMP1 expression for immune response.

 描述（由适用提供）：随着财务和技术支持的改善，许多疟疾内部分子国家再次将消除疟疾视为其国家控制疟疾的目标。为了实现这一雄心勃勃的目标，最大的挑战之一是开发血液阶段疫苗。 PFEMP1的抗原变异由60成员的VAR基因家族和在恶性疟原虫感染的红细胞表面表达的克隆表达的抗原变异是疟疾的关键病毒因子。尽管它在疟疾发病机理中的核心作用 无性血液阶段，Var基因相互排斥的表达的机制仍然很少理解，并且这种知识差距严重阻碍了杀死血液阶段寄生虫的新工具的开发。该项目建立在我们最近成功地创建所有VAR基因表达的恶性疟原虫线上的成功，旨在确定分子调节网络，并建立使用一组最近开发的遗传和表观遗传工具和资源的VAR基因调节机制的层次结构。这项研究产生的VAR基因调节因子的全面图景将使VAR基因家族在疟疾寄生虫的免疫进化中更好地了解VAR基因家族的抗原变异。该信息还将为理论提供新的目标，以阻止严重疟疾的PFEMP1介导的免疫进化或compplications，或增强疫苗最大化PFEMP1表达以获得免疫反应的能力。