Defining the novel eukaryotic biology of the Apicomplexan plastid

定义顶复体质体的新型真核生物学

基本信息

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
项目类别：
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

项目摘要

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重要质体细胞器。鉴于其独特的特征，顶端质体是这些寄生虫中新型真核生物学的来源，也是药物和疫苗开发的潜在致命弱点。利用顶端质体独特的生物学特性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两种重要人类病原体中顶质体的新途径和功能：疟原虫属寄生虫（全球领先的传染病杀手）和巴贝虫属寄生虫（一种威胁输血供应的新出现的人类感染）。在实现这一目标的重要一步中，我最近证明了血液阶段恶性疟原虫中顶端体的唯一基本功能是类异戊二烯的生物合成前身，IPP。因此，完全失去顶质体的恶性疟原虫可以通过补充 IPP 来挽救。值得注意的是，“apicoplast(-)”寄生虫的化学拯救使得本申请中概述的新方法和新实验成为可能。我研究了顶质体生物学的几个新方面：1) 鉴定蛋白质导入顶质体过程中关键且独特的步骤所需的蛋白质因子，2) 鉴定源自 IPP 的小分子类异戊二烯，这些小分子类异戊二烯可能在恶性疟原虫，3)巴贝虫寄生虫顶质体功能的测定，其与恶性疟原虫具有重要的致病和进化特征。这些目标的范围允许对 Apicoplexan 顶端质体的新特征进行彻底研究，这将产生令人着迷的真核生物学和有希望的治疗靶点。公共卫生相关性：顶复门寄生虫包括恶性疟原虫（人类最致命的疟疾的病因）和巴贝虫属寄生虫（对输血供应的新威胁），它们含有独特的质体细胞器，是药物开发的潜在致命弱点。在本申请中，我建议更好地了解细胞器的新生物学及其在发病机制中的作用。这项工作对于开发针对这些重要人类病原体的新疗法具有直接而重大的影响。