Defining the novel eukaryotic biology of the Apicomplexan plastid

定义顶复体质体的新型真核生物学

• 批准号: 8415677
• 负责人: Ellen Yeh
• 金额: $ 39.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415677
• 关键词: Anabolism; Antibiotics; Apicomplexa; Babesia; Babesiosis; Biology; Blood; Cell Nucleus; Cell physiology; Cells; Chemicals; Communicable Diseases; Complex; Development; Evolution; Genes; Goals; Human; Infection; Investigation; Label; Malaria; Mediating; Metabolic; Organelles; Organism; Output; Parasites; Pathogenesis; Pathway interactions; Plasmodium; Plasmodium falciparum; Plastids; Protein Import; Proteins; Research Personnel; Role; Sorting - Cell Movement; Source; Staging; Supplementation; Transfusion; Transport Vesicles; Vascular blood supply; Vesicle; Work; drug development; fascinate; isopentenyl pyrophosphate; isoprenoid; metabolomics; novel; novel strategies; novel therapeutics; pathogen; protein transport; research study; secretory protein; small molecule; therapeutic development; therapeutic target; vaccine development

DESCRIPTION (provided by investigator): Apicomplexan parasites contain an essential plastid organelle called the apicoplast. Given its unique features, the apicoplast is a source of novel eukaryotic biology in these parasites and a potential Achilles' heel for drug and vaccine development. The challenge in taking advantage of the apicoplast's unique biology for therapeutic development has been to identify the specific pathways and functions that can be targeted. My overall goal is to elucidate the novel pathways and functions of the apicoplast in two important human pathogens: Plasmodium spp parasites, a leading global infectious disease killer, and Babesia spp parasites, an emerging human infection that threatens the transfusion blood supply. In an important step towards this goal, I recently demonstrated that the sole essential function of the apicoplast in blood-stage P. falciparum is the biosynthesis of isoprenoid precursor, IPP. As such, P. falciparum parasites that have completely lost their apicoplast can be rescued by supplementation with IPP. Significantly, chemical rescue of "apicoplast(-)" parasites enables new approaches and novel experiments as outlined in this application. I investigate several novel aspects of apicoplast biology: 1) identification of protein factors required for a critical and unique step during protein import into the apicoplast, 2) identificatio of the small molecule isoprenoids derived from IPP that likely have essential cellular functions in P. falciparum, and 3) determination of the function of the apicoplast in Babesia parasites, which share important pathogenic and evolutionary features with P. falciparum. The scope of these aims allows a thorough investigation of the novel features of the Apicoplexan apicoplast that will yield fascinating eukaryotic biology and promising therapeutic targets. PUBLIC HEALTH RELEVANCE: Apicomplexan parasites which include Plasmodium falciparum, cause of the most deadly form of human malaria, and Babesia spp parasites, an emerging threat to the transfusion blood supply, contain a unique plastid organelle that is a potential Achilles' heel for drug development. In this application, I propose to better understand the novel biology of the organelle and its role in the pathogenesis. This work has direct and significant implications for development of novel therapeutics against these important human pathogens.

描述（由研究者提供）：顶复门寄生虫含有一种称为顶质体的基本质体细胞器。由于其独特的功能，顶质体是这些寄生虫中新的真核生物学的来源，也是药物和疫苗开发的潜在阿喀琉斯之踵。利用顶质体独特的生物学进行治疗开发的挑战是确定可以靶向的特定途径和功能。我的总体目标是阐明新的途径和功能的apicoplast在两个重要的人类病原体：疟原虫属寄生虫，一个领先的全球传染病杀手，和巴氏疟原虫属寄生虫，一个新兴的人类感染，威胁输血血液供应。在实现这一目标的重要一步中，我最近证明了血液期恶性疟原虫顶质体的唯一基本功能是类异戊二烯的生物合成 前体，IPP。因此，已经完全失去其顶质体的恶性疟原虫寄生虫可以通过补充IPP来拯救。重要的是，“顶质体（-）”寄生虫的化学拯救使得能够实现如本申请中概述的新方法和新实验。我研究了顶质体生物学的几个新方面：1）鉴定蛋白质进入顶质体过程中关键和独特步骤所需的蛋白质因子，2）鉴定来自IPP的小分子类异戊二烯，这些类异戊二烯可能在顶质体中具有重要的细胞功能。 P. 3）确定与恶性疟原虫具有重要致病性和进化特征的巴氏疟原虫顶质体的功能。这些目标的范围允许的Apicoplexan apicoplast，将产生迷人的真核生物学和有前途的治疗目标的新功能进行彻底的调查。 公共卫生相关性：顶复门寄生虫，包括恶性疟原虫，最致命的人类疟疾的原因，和巴氏疟原虫属寄生虫，一个新兴的威胁输血血液供应，含有一个独特的质体细胞器，是一个潜在的阿喀琉斯之踵药物开发。在这个应用程序中，我建议更好地了解新的生物学的细胞器及其在发病机制中的作用。这项工作对开发针对这些重要人类病原体的新疗法具有直接和重要的意义。