Toxoplasma Epigenomics and Gene Expression

弓形虫表观基因组学和基因表达

基本信息

批准号：
7950538
负责人：
Kami Kim
金额：
$ 64.28万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7950538
关键词：
Acquired Immunodeficiency Syndrome Affect Antigens Apicomplexa Biological Assay Cell Cycle Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Clinical Complex Cryptosporidium DNA DNA Binding Development Disease Drug Delivery Systems Encephalitis Environment Epidemic Epigenetic Process Event Family Family member Gene Activation Gene Expression Gene Expression Regulation Gene Structure General Transcription Factors Genes Genetic Genome Genomics Genotype Immune system Immunocompromised Host Individual Infection Lead Life Life Cycle Stages Macromolecular Complexes Mammals Maps Metabolism Modeling Molecular Mutagenesis Opportunistic Infections Organism Parasites Pathogenesis Patients Pattern Plant Genes Plants Protein Binding Proteins Proteomics Public Health Role Specificity Stress Surface Systems Biology TFAP2A gene Testing Toxoplasma Toxoplasma gondii Toxoplasmosis Transcription Factor AP-2 Alpha Virulence Work base chromatin modification combinatorial epigenomics interdisciplinary approach obligate intracellular parasite pathogen preference prevent programs promoter public health relevance response scaffold trait transcription factor

项目摘要

DESCRIPTION (provided by applicant): The obligate intracellular parasite Toxoplasma gondii is a major opportunistic pathogen of the AIDS epidemic. As it develops within host cells, the parasite implements a coordinated pattern of sequential gene expression. In response to stress and changes in its environment, the parasite completely alters its metabolism, surface antigens, and cell cycle to transition from tachyzoite to bradyzoite. Understanding how T. gondii regulates gene expression is fundamental for understanding the pathogenesis of toxoplasmosis. Epigenetic factors govern developmental transitions and expression of virulence traits, and are also implicated in T. gondii bradyzoite differentiation. How chromatin remodeling complexes interact with transcriptional machinery in T. gondii is not known. Recently, a plant-like transcription factor family, the APETELA 2 (or AP2) family, has been discovered and proposed as the primary transcription factors of T. gondii and other Apicomplexa. We hypothesize that conserved Apicomplexa AP2 family members have conserved functions in T. gondii as sequence-specific transcription factors that interact with general transcription factors and chromatin remodeling complexes to regulate gene expression. We have previously developed a epigenomic map of tachyzoites that defines functional regions of the genome. We will use this prior work to assist us in determining the genes regulated by TgAP2. The DNA binding specificity of AP2 proteins will be identified using a multidisciplinary approach. Proteins that interact with TgAP2 will be identified using proteomics. These studies will form a scaffold upon which we will build systems biology model to understand how gene networks govern biologically significant events such as bradyzoite formation. PUBLIC HEALTH RELEVANCE: Toxoplasma gondii is a parasitic pathogen that causes severe disease in immunocompromised individuals including people with AIDS. This parasite undergoes a carefully orchestrated developmental program within infected cells and also can respond to changes in its environment by changing into persistent, hardier bradyzoite forms. These transitions involve tight coordination of gene expression. Recently we have begun to characterize newly discovered T. gondii genes that appear to regulate gene expression. These genes, the AP2 family, may be new drug targets because they resemble plant genes rather than genes seen in mammals. The genes are also conserved in many other apicomplexan organisms that affect AIDS patients such as Cryptosporidium. Understanding the function of AP2 proteins may lead to new treatments that will prevent of treat T. gondii infection in individuals with AIDS.

描述（由申请人提供）：专性细胞内寄生虫弓形虫是艾滋病流行的主要机会病原体。当寄生虫在宿主细胞内发育时，它会实现顺序基因表达的协调模式。为了应对压力和环境变化，寄生虫完全改变其新陈代谢、表面抗原和细胞周期，从速殖子转变为缓殖子。了解弓形虫如何调节基因表达是了解弓形虫病发病机制的基础。表观遗传因素控制着发育转变和毒力性状的表达，并且也与弓形虫缓殖子的分化有关。染色质重塑复合物如何与弓形虫中的转录机制相互作用尚不清楚。最近，一个类植物转录因子家族，APETELA 2（或AP2）家族，被发现并被提议作为弓形虫和其他顶复门的主要转录因子。我们假设保守的 Apicomplexa AP2 家族成员在弓形虫中具有保守的功能，作为序列特异性转录因子，与一般转录因子和染色质重塑复合物相互作用以调节基因表达。我们之前开发了速殖子的表观基因组图谱，定义了基因组的功能区域。我们将利用之前的工作来帮助我们确定 TgAP2 调控的基因。 AP2 蛋白的 DNA 结合特异性将通过多学科方法进行鉴定。与 TgAP2 相互作用的蛋白质将使用蛋白质组学进行鉴定。这些研究将形成一个支架，我们将在此基础上构建系统生物学模型，以了解基因网络如何控制生物学上的重大事件，例如缓殖子的形成。公共卫生相关性：弓形虫是一种寄生病原体，可导致免疫功能低下的个体（包括艾滋病患者）患上严重疾病。这种寄生虫在受感染的细胞内经历精心策划的发育程序，并且还可以通过转变为持久的、更顽强的缓殖子形式来应对环境的变化。这些转变涉及基因表达的紧密协调。最近，我们开始表征新发现的弓形虫基因，这些基因似乎调节基因表达。这些基因（AP2 家族）可能成为新的药物靶标，因为它们类似于植物基因，而不是哺乳动物中的基因。这些基因在影响艾滋病患者的许多其他顶端复合体生物中也被保留，例如隐孢子虫。了解 AP2 蛋白的功能可能会带来新的治疗方法，从而预防或治疗艾滋病患者的弓形虫感染。