The AP2 factors required for Toxoplasma replication

弓形虫复制所需的 AP2 因子

基本信息

批准号：
8811088
负责人：
Michael W White
金额：
$ 42.78万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811088
关键词：
Acute Disease Animals Apicomplexa Area Attention Binding Binding Sites Biological Assay Biology Biomass Cell Cycle Cell Cycle Regulation Cell Nucleus Cells Cessation of life Complex Critical Pathways Cytolysis DNA Binding DNA Microarray Chip DNA Sequence DNA-Binding Proteins Daughter Disease Drug Targeting Elements Ensure Epitopes Family Gene Expression Gene Expression Profile Gene Targeting Generations Genes Genetic Programming Genetic Transcription Genome Goals Growth Host Defense Human Immunocompromised Host In Vitro Individual Infection Inflammation Insertional Mutagenesis Knowledge Lead Life Cycle Stages Link Location Maps Messenger RNA Modeling Molecular Parasite Control Parasites Pathogenesis Phenotype Plants Plasmodium Positioning Attribute Process Protein Binding Proteins Regulation Research Role Severity of illness Staging TFAP2A gene Time Tissues Toxoplasma Toxoplasma gondii Transcription Factor AP-2 Alpha Validation Virulence asexual base body system burden of illness cdc Genes chromatin immunoprecipitation genetic analysis global health in vivo mRNA Expression mutant novel obligate intracellular parasite parasite invasion pathogen programs promoter protein function research study trait transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Apicomplexan parasites are important pathogens of humans that cause diseases with widespread impacts on global health. The life cycles of these obligate intracellular parasites are complex, involving multiple proliferative and non-growing stages that ensure successful parasite transmission. Pathogenesis, virulence, and disease severity are critically influenced by asexual stage growth rates that can lead to increased parasite biomass and significant tissue destruction and inflammation. Consequently, mechanisms controlling parasite growth rate are important to virulence. Building new daughter parasites requires tight control over the delivery of protein products, and in Plasmodium and Toxoplasma a cascade of >2800 mRNAs serially unfolds during each division cycle. Transcription in apicomplexa pathogens is poorly understood, however, the recent discovery of plant-like transcription factors in the Apicomplexa has uncovered an important set of factors that may control cell cycle transcription in these parasites. Nearly a third of all Toxoplasma AP2 genes are periodically expressed during tachyzoite replication with a timing distributed across the division cycle. We hypothesize that these factors are responsible for the "just-in-time" delivery of gene products required to build new parasites. Through their binding to specific promoter DNA sequence, TgAP2 factors regulate cell cycle transcription, and thereby influence the efficiency and fidelity of Toxoplasma replication. In this proposal, we will characterize the role of TgAP2 factors in the parasite cell cycle by determining the precise order of expression for key cell cycle TgAP2 proteins, by discovering the promoters they regulate through whole-genome protein binding studies, and by validating the in vivo function of these proteins in parasite replication through the generation of loss and mis- expression mutants. These studies will provide fundamental knowledge of a new set of mechanisms required to produce parasite replication that is relevant to acute disease caused by the growth of Toxoplasma in the immunocompromised human host.

描述（由申请人提供）：Apicomplexan寄生虫是人类的重要病原体，引起对全球健康产生广泛影响的疾病。这些强制性细胞内寄生虫的生命周期是复杂的，涉及多个增殖和非生长阶段，可确保成功的寄生虫传播。发病机理，毒力和疾病的严重程度受到无性阶段生长速率的严重影响，这会导致寄生虫生物量增加，并大大的组织破坏和炎症。因此，控制寄生虫生长速率的机制对于毒力很重要。建立新的女儿寄生虫需要严格控制蛋白质产品的递送，在疟原虫和弓形虫中，在每个分裂周期中串行串行的mRNA级联反应。但是，对Apicomplexa病原体的转录尚不清楚，但是，最近发现Apicomplexa中类似植物的转录因子的转录发现了一组重要的因子，这些因素可能控制这些寄生虫中的细胞周期转录。所有弓形虫AP2基因的几乎三分之一在速度复制期间定期表达，并在整个分裂周期中分布着时间。我们假设这些因素是造成建立新寄生虫所需的基因产品的“及时”输送的原因。通过与特定启动子DNA序列的结合，TGAP2因子调节细胞周期转录，从而影响弓形虫复制的效率和保真度。在该提案中，我们将通过确定关键细胞周期TGAP2蛋白的精确表达顺序来表征TGAP2因子在寄生细胞周期中的作用，并通过发现它们通过全基因组蛋白结合研究调节的启动子，并通过验证这些蛋白质在寄生虫复制中通过产生损失和误差表达突变的体内功能来调节这些蛋白质的功能。这些研究将提供有关产生寄生虫复制所需的新机制的基本知识，这些机制与免疫功能低下的人类宿主中毒素的生长引起的急性疾病有关。