The Plastid of Toxoplasma gondii

弓形虫质体

• 批准号: 7795244
• 负责人: Marilyn Parsons
• 金额: $ 47.27万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795244
• 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（由申请人提供）：弓形虫弓形虫是一种重要的机会性病原体，影响了全球多达三分之一的未经治疗的艾滋病患者。该寄生虫具有一个独特而必不可少的细胞器，称为Apicoplast，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apicoplast是抗寄生虫发展的重要潜在靶标。关于该细胞器的生物发生知之甚少，该细胞器是四个膜界定的。到目前为止，仅探索了针对apicoplast Lumen的靶向。此类蛋白质是由信号序列提供的，该信号序列允许进入分泌系统和将其从ER伸向质体的过境肽。我们提出了挑衅性的证据，即后一个步骤以高尔基独立的方式发生。在过去的赠款期间，我们确定了两种apicoplast膜蛋白（一种转运蛋白和一个蛋白酶），它们都缺乏规范的靶向序列。与腔蛋白相比，这些蛋白显示出细胞周期依赖于凋亡的定位。由于这些差异以及独特的最终目的地，因此介导非亮蛋白靶向的途径和序列可能涉及新元素。该提案概述了旨在表征一组局部局部到各种apicoplast室的蛋白质的实验，并将剖析对于这些蛋白质正确定位至关重要的机制和序列。我们还将确定靶向apicoplast膜蛋白的靶向是由已知参与ER出口过程的分子还是靶向Golgi贩运。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，并提供有关其功能的其他信息。公共卫生相关性该项目建议检查寄生虫弓形虫巨质的植物样细胞器，该细胞器称为apicoplast，这是一种药物，该药物在怀孕期间获得免疫功能低下的个体和出生缺陷，导致脑炎。由于人类缺乏植型群，它为寄生虫提供了新的干预措施的潜在目标。