The Plastid of Toxoplasma gondii

弓形虫质体

• 批准号: 8070872
• 负责人: Marilyn Parsons
• 金额: $ 1.86万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-24 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070872
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Algae; Binding; Biogenesis; Bioinformatics; Bypass; Cell Cycle; Chloroplasts; Congenital Abnormality; Destinations; Development; Disease; Elements; Encephalitis; Endoplasmic Reticulum; Epitopes; Event; Genes; Goals; Golgi Apparatus; Grant; Human; Immunocompromised Host; Individual; Intervention; Maintenance; Mediating; Membrane; Membrane Fusion; Membrane Proteins; Membrane Transport Proteins; Methods; Mutagenesis; N-terminal; Nuclear; Organelles; Parasites; Patients; Peptide Hydrolases; Peptide Signal Sequences; Peptides; Phagosomes; Plants; Plastids; Pregnancy; Process; Protein Import; Proteins; Route; Set protein; Site; Structure; System; Thioredoxin; Time; Toxoplasma gondii; improved; inhibitor/antagonist; luminal membrane; novel; pathogen; public health relevance; rab GTP-Binding Proteins; research study; trafficking

DESCRIPTION (provided by applicant): Toxoplasma gondii is an important opportunistic pathogen, affecting up to one-third of untreated AIDS patients worldwide. The parasite possesses a unique and essential organelle called the apicoplast, which is genetically and functionally related to chloroplasts. Because the human host lacks a similar organelle, the apicoplast is an important potential target for development of anti-parasitic agents. Little is known about the biogenesis of this organelle, which is bounded by four membranes. Until now, only targeting to the apicoplast lumen has been explored. Such proteins are targeted courtesy of a signal sequence that allows entry into the secretory system and a transit peptide that routes them from the ER to the plastid. We have presented provocative evidence that the latter step occurs in a Golgi- independent manner. In the past grant period we identified two apicoplast membrane proteins (a transporter and a protease), both of which lack canonical targeting sequences. In contrast to luminal proteins, these proteins show cell cycle dependent localization to the apicoplast. Because of these differences as well as the distinct ultimate destinations, the routes and sequences that mediate targeting of non-luminal proteins likely involve novel elements. This proposal outlines experiments aimed at characterizing a set of proteins localized to various apicoplast compartments, and will dissect the mechanisms and sequences important for the proper localization of these proteins. We will also determine whether targeting of apicoplast membrane proteins is assisted by molecules known to be involved in ER exit processes or ER to Golgi trafficking. These studies will expand our understanding of the biogenesis of this unique organelle and provide additional information concerning its function. PUBLIC HEALTH RELEVANCE This project proposes to examine a plant-like organelle called the apicoplast in the parasite Toxoplasma gondii, an agent which causes encephalitis in immunocompromised individuals and birth defects when acquired during pregnancy. As humans lack an apicoplast, it provides a potential target for new interventions against the parasite.

描述(申请人提供)：弓形虫是一种重要的机会性病原体，影响全球三分之一未经治疗的艾滋病患者。这种寄生虫有一个独特而重要的细胞器，称为叶绿体，在遗传和功能上与叶绿体相关。由于人类宿主缺乏类似的细胞器，因此顶生质体是开发抗寄生虫剂的重要潜在靶点。人们对这种细胞器的生物发生知之甚少，它由四层膜包围。到目前为止，只有针对顶生质体管腔的研究才被探索。这些蛋白质的靶标是一个信号序列和一个转运肽，前者允许进入分泌系统，后者将它们从内质网引导到叶绿体。我们提出了挑衅性的证据，证明后一步是以一种不依赖高尔基人的方式发生的。在过去的资助期间，我们鉴定了两种质膜蛋白(一种转运蛋白和一种蛋白酶)，这两种蛋白都缺乏规范的靶向序列。与腔蛋白不同的是，这些蛋白与细胞周期相关，定位于细胞顶体。由于这些差异以及不同的最终目的地，介导非管腔蛋白靶向的路线和序列可能涉及新的元件。这项建议概述了旨在表征一组定位于不同质外体隔间的蛋白质的实验，并将剖析对这些蛋白质的正确定位至关重要的机制和序列。我们还将确定质膜蛋白的靶向是由已知的参与内质网退出过程的分子辅助的，还是由内质网向高尔基体运输的。这些研究将扩大我们对这种独特细胞器的生物发生的理解，并提供关于其功能的更多信息。公共卫生相关性该项目建议检查寄生虫弓形虫中一种名为质外体的植物状细胞器，弓形虫是一种在怀孕期间感染时会导致免疫受损个体脑炎和出生缺陷的病原体。由于人类缺乏质外体，它为针对这种寄生虫的新干预措施提供了一个潜在的靶点。