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（由申请人提供）：随着资金和技术支持的改善，许多疟疾流行国家再次将消除疟疾作为其国家疟疾控制目标。为了实现这一宏伟目标，最大的挑战之一是血期疫苗的开发。 PfEMP1 的抗原变异由 60 个成员的 var 基因家族编码，在恶性疟原虫感染的红细胞表面克隆表达，是疟疾的关键毒力因子。尽管它在疟疾发病机制中发挥着核心作用 在无性血液阶段，var基因相互排斥的表达机制仍然知之甚少，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创建表达所有 var 基因的恶性疟原虫系的基础上，旨在利用一套最近开发的遗传和表观遗传工具和资源确定分子调控网络并建立 var 基因调控机制的层次结构。本研究产生的 var 基因调控因子的全面图景将有助于更好地了解 var 基因家族在疟原虫免疫逃避中的抗原变异。这些信息还将为治疗方法提供新的靶标，以阻止 PfEMP1 介导的免疫逃避或严重疟疾并发症，或增强疫苗最大限度地提高 PfEMP1 表达以产生免疫反应的能力。