Defining the novel eukaryotic biology of the Apicomplexan plastid

描述(由研究人员提供)：Apicomplexan寄生虫包含一种称为顶生质体的基本质体细胞器。鉴于其独特的特性，顶体是这些寄生虫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。在利用质外体独特的生物学进行治疗开发方面的挑战一直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的人类病原体：疟原虫寄生虫和巴贝斯虫寄生虫的新途径和功能。前者是全球领先的传染病杀手，后者是一种威胁输血供应的新兴人类感染。在朝着这一目标迈出的重要一步中，我最近证明了恶性疟原虫血液期顶生质体的唯一基本功能是生物合成类异戊二烯。 前体，IPP。因此，已经完全失去质外体的恶性疟原虫可以通过补充IPP来拯救。值得注意的是，化学拯救“顶体(-)”寄生虫使新的方法和新的实验成为可能，如本申请中所概述的。我研究了质外体生物学的几个新方面：1)鉴定在蛋白质进入质外体过程中一个关键而独特的步骤所需的蛋白质因子，2)鉴定来自IPP的小分子异戊二烯类化合物，它可能在 以及3)巴贝斯虫顶生质体功能的测定，它们与恶性疟原虫有重要的致病和进化特征。这些目标的范围允许对apicopexan顶生质体的新特征进行彻底的研究，这些特征将产生迷人的真核生物学和有希望的治疗靶点。 公共卫生相关性：Apicomplexan寄生虫，包括导致人类最致命形式疟疾的恶性疟原虫，以及巴贝斯虫寄生虫，对输血供应构成新的威胁，含有一种独特的叶绿体细胞器，这是药物开发的潜在致命弱点。在这一应用中，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。

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.