Epigenetic reprogramming of the malaria parasite

疟疾寄生虫的表观遗传重编程

• 批准号: 9979071
• 负责人: ELISABETH D MARTINEZ
• 金额: $ 24.48万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-17 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979071
• 关键词: 5 year old; Adhesions; Affect; Alleles; Antigenic Variation; Antimalarials; Area; Automobile Driving; Biology; Blood; Cells; Cessation of life; Chemistry; Child; Culicidae; Data; Disease; Drug resistance; Enzymes; Epigenetic Process; Erythrocytes; Event; Excision; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Histones; Human; Immune Evasion; Individual; Libraries; Life Cycle Stages; Link; Liver; Lysine; Malaria; Membrane Proteins; Methylation; Mixed Function Oxygenases; Molecular; Multigene Family; Nutrient; Parasites; Pathologic; Pathology; Pathway interactions; Pattern; Permeability; Pharmacology; Plasmodium falciparum; Plasmodium falciparum genome; Play; Proteins; Recombinants; Regulation; Repression; Resistance development; Role; Specificity; Switch Genes; Transcriptional Regulation; Virulent; analog; asexual; demethylation; drug discovery; enhancer-binding protein AP-2; enzyme activity; genomic locus; histone demethylase; histone methylation; in vitro activity; in vivo; inhibitor/antagonist; interest; novel; novel therapeutics; overexpression; paralogous gene; screening; small molecule; small molecule inhibitor; transcription factor; uptake

Plasmodium falciparum (Pf) is the most lethal of the five species of malaria affecting 3.4 billion humans annually. The Pf life cycle consists of a single round of sexual and asexual replication in the mosquito gut and human liver, respectively, followed by multiple rounds of asexual replication in human red blood cells (RBCs). Proper transcriptional regulation at each stage is essential for the successful completion of the life cycle, for gametocytogenesis and for RBC invasion. Epigenetic enzymes are thought to play important and potentially essential roles in this regulation. The methylation state of histones at specific genomic loci, for example, controls the expression of stage-specific transcription factors such as AP2-G, of nutrient uptake channels including the Clag3 gene paralogs, and of mono-allelically expressed multi-gene families such as the highly virulent var genes that encode adhesion proteins involved in antigenic variation. These loci are kept transcriptionally repressed by trimethylation of lysine 9 on histone 3 (H3K9me3). Proper temporal activation of these loci or switching to a distinct gene form for antigenic variation requires the enzymatic removal of this H3K9me3 transcriptional silencing mark. Similarly, proper temporal repression of active genes marked by H3K4me3 such as transcriptionally active stage-specific genes or mono-allelic loci for gene switching, requires erasing the activating H3K4me3 mark. Demethylation of trimethylated histones such as H3K9me3 or H3K4me3 can only be carried out by Jumonji domain containing histone hydroxylases. No other proteins with this activity are known in biology to date. The Pf genome encodes three Jumonji hydroxylases: PfJmjC1, PfJmjC2 and PfJmj3. We propose that the aggregate activity of these enzymes is essential to Pf viability. We have a long standing interest in defining and pharmacologically modulating Jumonji enzyme function. Our Specific Aims here are: Aim 1: To characterize the anti-malaria mechanism of action of three potent & selective novel Jumonji demethylase inhibitors we have identified in an anti-malaria screen Aim 2: To determine the function of the three putative malaria Jumonji histone demethylases (focusing on PfJmj3 whose function has never been studied) This proposal will establish links between the molecular players driving malaria epigenetic pathways and events that cause pathology and immune evasion in humans, and will create a novel therapeutic pipeline of potential anti-malarial compounds targeting putative parasite Jumonji domain-containing epigenetic enzymes.

恶性疟原虫(PF)是影响34亿人的五种疟疾中最致命的 每年一次。PF的生命周期包括蚊子肠道和蚊子体内的单轮有性和无性复制 分别在人类肝脏中进行了多轮无性复制，然后在人类红细胞(RBC)中进行了多轮无性复制。 在每个阶段适当的转录调控对于成功完成生命周期是必不可少的，对于 配子体发生和红细胞入侵。表观遗传酶被认为起着重要的和潜在的作用 在这项规定中扮演的重要角色。组蛋白在特定基因组位置的甲基化状态，例如， 控制营养吸收通道的阶段特异性转录因子如AP2-G的表达 包括Clag3基因平行序列，以及单等位基因表达的多基因家族，如高度 编码黏附蛋白的毒力var基因参与了抗原变异。这些轨迹被保存下来 组蛋白3(H3K9me3)上赖氨酸9的三甲基化抑制转录。适当的时间激活 这些基因座或切换到不同的基因形式以进行抗原变异需要酶促移除 H3K9me3转录沉默标记。同样，对活性基因的适当时间抑制也具有以下特征 H3K4me3，如转录活跃的阶段特异基因或用于基因切换的单等位基因，需要 擦除激活的H3K4me3标记。三甲基化组蛋白如H3K9me3或H3K4me3的去甲基化 只能由含有组蛋白羟基酶的Jumonji结构域执行。没有其他具有这种活性的蛋白质 都是迄今为止在生物学中已知的。Pf基因组编码三种Jumonji羟基酶：PfJmjC1、PfJmjC2和 PfJmj3.我们认为，这些酶的总活性对PF的生存是至关重要的。我们有很长一段时间 对Jumonji酶功能的定义和药理调节一直感兴趣。我们的具体目标 以下是： 目的1：研究三种强效选择性新药菊梦集的抗疟疾作用机制 我们在抗疟疾筛查中发现的去甲基酶抑制剂 目的2：确定三种可能的疟疾Jumonji组蛋白去甲基酶的功能(聚焦 关于功能从未被研究过的PfJmj3) 这项提议将在推动疟疾表观遗传途径的分子参与者和 导致人类病理和免疫逃避的事件，并将创建一条新的治疗管道 针对可能的寄生虫Jumonji结构域包含表观遗传酶的潜在抗疟疾化合物。