Transcription factor control of Entamoeba development

内阿米巴发育的转录因子控制

• 批准号: 8950071
• 负责人: UPINDER SINGH
• 金额: $ 19.77万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8950071
• 关键词: Amoeba genus; Area; Binding; Binding Proteins; Binding Sites; Biological Models; Biology; Cause of Death; Cyst; DNA; Data; Development; Disease; Dominant-Negative Mutation; Down-Regulation; Dysentery; EMSA; Entamoeba; Entamoeba histolytica; Entamoeba invadens; Etiology; Exploratory/Developmental Grant; Family; Gene Expression; Gene Expression Profile; Genes; Genetic; Genome; Genomic approach; Goals; Grant; Health; Human; In Vitro; Knowledge; Life Cycle Stages; Liver Abscess; Methods; Molecular; Nature; Organism; Oxidative Stress; Parasites; Pathogenesis; Pathway interactions; Phenotype; Process; Protein Binding; Proteins; Protocols documentation; Publications; RNA Interference; Role; Signal Transduction; Staging; System; Tissues; Transcriptional Regulation; Transfection; Virulence; Work; base; biological adaptation to stress; disease transmission; enteric pathogen; excystation; experience; genetic approach; genetic manipulation; high risk; insight; metabolomics; method development; new therapeutic target; novel; pathogen; prevent; promoter; public health relevance; success; tool development; transcription factor; transmission process

 DESCRIPTION (provided by applicant): Entamoeba histolytica, a protozoan parasite, is an important human pathogen. Diseases caused by E. histolytica include dysentery and liver abscesses, and this organism is a leading parasitic cause of death on a global scale. The life cycle of Entamoeba involves stage inter-conversion between trophozoites and cysts. Importantly, the conversion to cysts allows the pathogen to disseminate to new hosts while development to trophozoites allows the organism to cause invasive disease in the host. Thus, stage interconversion is essential for disease transmission and pathogenesis. However, despite being central to amebic biology, stage conversion is poorly understood. Many factors have contributed to the paucity of data including the inability to reproduce the developmental cycle in E. histolytica. Instead, the reptilian ameba E. invadens, which has the same disease pathogenesis as E. histolytica, has been used as a model system to study Entamoeba development. In E. invadens, both encystation and excystation can be recapitulated with high efficiency in vitro. However, until recently a poorly annotated genome and lack of methods for genetic manipulation have prevented full exploitation of this system. The recent re-sequencing of the E. invadens genome, publication of the transcriptome of stage conversion, and development of methods for constitutive and regulated gene expression open up new avenues for discovery. We aim to build upon these recent successes by studying transcription factors that regulate stage conversion as a means to identify pathways that regulate encystation. We will (i) characterize two known transcription factors to determine their roles in controlling stage conversion, and (ii) identify a new transcription factor that controls genes regulated during early encystation. These data will allow us to gain the first insights into the molecular mechanisms that regulate Entamoeba development and could give important insights into methods for blocking this transition or new targets for therapeutics. Dissecting the developmental cascade is crucial to understanding the biology of this important human pathogen.

 描述（由申请方提供）：溶组织内阿米巴是一种原生动物寄生虫，是一种重要的人类病原体。E.溶组织菌包括痢疾和肝脓肿，这种生物体是全球范围内主要寄生虫致死原因。内阿米巴的生活史包括滋养体和包囊之间的阶段相互转换。重要的是，转化为包囊允许病原体传播到新的宿主，而发育为滋养体允许生物体在宿主中引起侵入性疾病。因此，阶段转换对于疾病传播和发病是必不可少的。然而，尽管是核心阿米巴生物学，阶段转换是知之甚少。许多因素导致了数据的缺乏，包括不能再现E。溶组织剂相反，爬行动物阿米巴E. invadens的致病机理与E. histolytica已被用作研究内阿米巴发育的模型系统。在大肠在体外，无论是包囊还是脱囊，都可以高效地再现入侵体。然而，直到最近，一个注释不佳的基因组和缺乏遗传操作的方法，阻止了充分利用这一系统。最近对E. invadens基因组，阶段转换转录组的出版，以及组成型和调控基因表达方法的发展，为发现开辟了新的途径。我们的目标是建立在这些最近的成功，通过研究转录因子，调节阶段转换作为一种手段，以确定途径，调节成囊。我们将（i）表征两个已知的转录因子，以确定它们在控制阶段中的作用， 转换，和（ii）确定一个新的转录因子，控制基因调节，在早期 包囊形成。这些数据将使我们能够首次深入了解调节内阿米巴发育的分子机制，并可能为阻断这种转变的方法或治疗的新靶点提供重要见解。剖析发育级联对于理解这种重要的人类病原体的生物学至关重要。