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Molecular mechanisms of schizogony in malaria parasites

疟原虫分裂的分子机制

基本信息

批准号：
9797203
负责人：
JEFFREY D DVORIN
金额：
$ 61.72万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9797203
关键词：
5 year old Address Alleles Apical Automobile Driving Binding Biochemical Biogenesis Biological Biological Assay Biological Process Blood Cell Nucleus Cell membrane Cell physiology Cells Centrosome Cessation of life Child Chromosome Condensation Clinical Co-Immunoprecipitations Complex Cytokinesis Cytoplasm Data Daughter Defect Development Dynamin Erythrocytes Excision Failure Future Genetic Goals Guanosine Triphosphate Phosphohydrolases Human Individual Infection Investigation Knowledge Label Learning Link Lipid Bilayers Malaria Mediating Membrane Molecular Morbidity - disease rate Names Organelles Parasites Pathway interactions Plasmodium Plasmodium falciparum Process Proteins Public Health Recombinant Proteins Resolution Role Shapes Site Structure System Techniques Testing Therapeutic Video Microscopy Work asexual condensin experimental study improved knock-down molecular marker mortality mutant novel nuclear division protein complex protein protein interaction recruit reverse genetics

项目摘要

PROJECT SUMMARY Malaria is an important cause of illness and death worldwide, with most of these deaths resulting from Plasmodium falciparum infection. Clinical malaria results from the asexual replication of parasites in human red blood cells. During the blood stage, P. falciparum replicates via schizogony, wherein daughter parasites are formed by a specialized cytokinesis known as segmentation. The inner membrane complex (IMC), a unique structure within the parasite composed of parasite proteins and a double lipid bilayer that is closely associated with the plasma membrane, and associated basal complex are hypothesized to orchestrate daughter parasite assembly and division. The focus of the current application is on the molecular mechanisms of schizogony and segmentation. Directed experiments will determine the biogenesis, composition, and function of the IMC and basal complex. We have discovered two novel parasites that are essential for schizogony and segmentation. The first, PfMOP, localizes initially near the centrosome and later to the apical end of the parasite and is critical for IMC biogenesis. The second, PfCINCH, localizes to the basal complex and is critical for parasite cytokinesis. These two proteins allow interrogation of the IMC and basal complex from the apical and basal ends of the parasite, respectively. The recently discovered P. falciparum Merozoite Organizing Protein is essential for both asexual and gametocyte development. In PfMOP-deficient parasites, the IMC does not form properly, resulting in a failure of segmentation, and the incompletely segmented merozoites remain in an agglomerate with a common cytoplasm. The molecular function of PfMOP and its link to the progression of schizogony and IMC biogenesis remain unknown. The proposed studies address these critical knowledge gaps. The first aim is divided into three independent subaims. In Aim 1.1, the link between PfMOP and IMC biogenesis in late schizogony will be investigated using a cell biologic approach with live video microscopy. In Aim 1.2, the function of PfMOP in early schizonts will be investigated, testing the hypothesis that PfMOP recruits a critical protein complex for chromosome condensation. In Aim 1.3, the PfMOP protein interactions in late schizonts will be determined, validated, and functionally evaluated by reverse-genetics. PfCINCH (Coordinator of nascent cell detachment) is a novel and essential component of the basal complex. In PfCINCH-deficient parasites, the final stages of segmentation are disrupted. In the second aim of this proposal, we focus on the cellular function of PfCINCH and its protein-protein interactions. The long-term objectives and public health implications of these studies are to identify critical biologic process pathways in the malaria parasite that could be targeted by future therapeutics.

项目概要疟疾是全世界疾病和死亡的重要原因，其中大部分死亡是由疟疾引起的恶性疟原虫感染。临床疟疾是人体寄生虫无性复制的结果红细胞。在血液阶段，恶性疟原虫通过分裂生殖进行复制，其中子代寄生虫由称为分割的特殊胞质分裂形成。内膜复合体 (IMC) 寄生虫内的独特结构由寄生虫蛋白和紧密结合的双脂双层组成与质膜相关，以及相关的基底复合物被假设协调女儿寄生虫的组装和分裂。目前应用的重点是分子分裂和分割的机制。定向实验将确定生物发生， IMC 和基础复合体的组成和功能。我们发现了两种新的寄生虫对于分裂和分割至关重要。第一个是 PfMOP，最初位于中心体附近，随后到达寄生虫的顶端，对于 IMC 生物发生至关重要。第二个 PfCINCH 定位于基础复合体，对寄生虫胞质分裂至关重要。这两种蛋白质允许询问 IMC 和基底复合体分别来自寄生虫的顶端和基底端。最近发现的恶性疟原虫裂殖子组织蛋白对于无性繁殖和有性繁殖都至关重要。配子体发育。在 PfMOP 缺陷的寄生虫中，IMC 无法正常形成，导致分割失败，不完全分割的裂殖子仍以团块形式存在共同的细胞质。 PfMOP 的分子功能及其与分裂和 IMC 进展的联系生物发生仍然未知。拟议的研究解决了这些关键的知识差距。第一个目标是分为三个独立的子目标。在目标 1.1 中，PfMOP 与晚期 IMC 生物发生之间的联系将使用细胞生物学方法和实时视频显微镜来研究分裂。在目标 1.2 中，将研究 PfMOP 在早期裂殖体中的功能，检验 PfMOP 招募染色体浓缩的关键蛋白质复合物。在目标 1.3 中，后期 PfMOP 蛋白相互作用裂殖体将通过反向遗传学进行确定、验证和功能评估。 PfCINCH （新生细胞脱离的协调者）是基底复合体的一种新颖且重要的组成部分。在 PfCINCH 缺陷的寄生虫，分割的最后阶段被破坏。在本次活动的第二个目标中提案中，我们重点关注 PfCINCH 的细胞功能及其蛋白质-蛋白质相互作用。长期来看这些研究的目标和公共卫生影响是确定关键的生物过程途径未来治疗方法可能针对的疟疾寄生虫。