Epigenetic reprogramming of the malaria parasite

疟疾寄生虫的表观遗传重编程

基本信息

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
项目类别：
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

项目摘要

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34亿人类的五种疟疾中最致命的每年。 PF生命周期由蚊子中的一轮性和无性复制组成，人肝，随后在人红细胞（RBC）中进行了多轮无性复制。在每个阶段进行适当的转录调节对于成功完成生命周期至关重要配子细胞生成和RBC入侵。表观遗传酶被认为发挥重要性并且可能发挥作用在此法规中的重要作用。例如控制营养吸收通道的阶段特异性转录因子（例如AP2-G）的表达包括clag3基因旁系同源物和单相表达的多基因家族，例如高度编码涉及抗原变异的粘附蛋白的毒物VAR基因。这些基因座保存在组蛋白3（H3K9me3）上赖氨酸9的三甲基化受到转录抑制。适当的时间激活这些基因座或切换到抗原变异的独特基因形式需要酶促去除此 H3K9ME3转录沉默标记。同样，适当地抑制主张的活性基因 H3K4ME3，例如转录活性阶段特异性基因或用于基因开关的单相关基因座，需要擦除活化的H3K4me3标记。三甲基化组蛋白的去甲基化，例如H3K9Me3或H3K4Me3 只能由含有组蛋白羟化酶的Jumonji结构域进行。该活动没有其他蛋白质迄今为止在生物学上已知。 PF基因组编码三个Jumonji羟基酶：PFJMJC1，PFJMJC2和 PFJMJ3。我们建议这些酶的骨料活性对于PF生存能力至关重要。我们有很长的对定义和药理调节Jumonji酶功能的兴趣。我们的具体目标这是：目标1：表征三种有效和选择性小说Jumonji的反马拉里亚作用机理脱甲基酶抑制剂我们已经在抗马拉里亚筛查中鉴定出来目标2：确定三种假定的疟疾Jumonji组蛋白脱甲基酶的功能（聚焦在从未研究的功能的PFJMJ3上）该建议将在驱动疟疾表观遗传途径的分子玩家和引起人类病理学和免疫逃避的事件，并将创建新的治疗管道潜在的抗疟疾化合物靶向推定的寄生虫Jumonji结构域的表观遗传酶。