A Systems Biology Approach to the Model Apicomplexan Toxoplasma gondii

弓形虫顶复门模型的系统生物学方法

• 批准号: 8048844
• 负责人: Kami Kim
• 金额: $ 563.02万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048844
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Animal Model; Apicomplexa; Area; Binding; Biological Models; C-terminal; Categories; Cessation of life; Chromatin; Cloning; Collection; Communicable Diseases; Communities; Complementary DNA; Complex; Congenital Abnormality; Cryptosporidium; DNA Binding; DNA Binding Domain; Data; Data Set; Development; Diabetes Mellitus; Disease; Disease Outbreaks; Drug Delivery Systems; Environment; Epidemic; Epigenetic Process; Epitopes; Essential Genes; Eukaryotic Cell; Functional disorder; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genome; Genomics; Goals; Human; Immunocompromised Host; Individual; Knock-out; Ligation; Macromolecular Complexes; Malaria; Medical; Metabolism; Mining; Modeling; Molecular Biology; Parasites; Pathology; Plasmodium; Population; Protein Binding; Proteins; Proteomics; Public Health; Resources; Specificity; System; Systems Biology; Testing; Toxoplasma; Toxoplasma gondii; Transcription factor genes; Translating; Vaccines; Virulence; base; biodefense; combinatorial; disorder prevention; epigenomics; expression vector; genome sequencing; genome-wide; global health; high throughput technology; human disease; innovation; insight; multidisciplinary; novel; obligate intracellular parasite; pathogen; prevent; protein expression; public health relevance; response; trait; transcription factor; treatment strategy; waterborne

DESCRIPTION (provided by applicant): This application focuses upon the Apicomplexa, etiologic agents of many diseases in the developing world and relevant to global health (thematic area 4). It uses genomics and other high throughput technologies (thematic area 1) with a systems-level integration, analysis and mining of large datasets with the overarching goal of translating our discoveries into new insights into therapy and disease prevention (thematic area 2). To accomplish our goals, we have assembled a multidisciplinary collaborative team with expertise in infectious diseases, diabetes, metabolism, pathology, molecular biology, animal models and pathophysiology to conduct an innovative study in challenging biomedical areas (thematic area 5). As major emerging and reemerging pathogens, Apicomplexan parasites infect more than a third of the world's population. These obligate intracellular parasites include Toxoplasma gondii, Plasmodium species and Cryptosporidium. Toxoplasma gondii is a major opportunistic pathogen of the AIDS epidemic, a cause of birth defects and is also a Category B priority agent due to its association with waterborne outbreaks. Plasmodium species, the agents of malaria, infect over 267 million people per year and cause nearly 1 million deaths per year. Despite the importance of these parasites in human disease, there are no effective vaccines for these pathogens, and new strategies for treatment and prevention of disease are needed. Very little is understood how the Apicomplexa regulate virulence traits and respond to changes in their environment. The development of new high-throughput technologies has enabled collection of large genomic and proteomics datasets. These can be used to develop an integrated understanding of how eukaryotic cells regulate gene expression. We will take advantage of genome manipulation, genome-wide arrays, high throughput sequencing, and proteomics to develop datasets that will facilitate an integrated systems approach to understanding regulation of gene expression and epigenetics in the model apicomplexan T.gondii. We will test the essentiality of chromatin remodellers and candidate transcription factors using a moderate through-put gene disruption strategy. Using epitope tagged chromatin remodelers and transcription factors, we will use high throughput sequencing of chromatin immunoprecipitates and expression microarrays to identify groups of co-regulated genes. Finally, we will perform high-throughput proteomics to characterize the constituents of macromolecular complexes involved in regulation of gene expression. These epigenomic, transcriptome, and proteomic datasets will facilitate computational approaches to model how epigenetic and genetic factors in the Apicomplexa interact within gene networks. This effort will create important community resources to enable a systems biology approach toward understanding expression of virulence traits and identification of novel drug targets for apicomplexan parasites. PUBLIC HEALTH RELEVANCE: Toxoplasma gondii is a parasitic pathogen that causes severe disease in immunocompromised individuals including people with AIDS, causes birth defects, and is a Biodefense Category B pathogen due to its association with waterborne outbreaks. Finally it is a model system for other parasites like Plasmodium, which cause human malaria. These parasites affect over a third of the world's population. We are trying to generate large datasets that will help us understand how these parasitic pathogens change in response to interaction with human hosts and how they regulate genes that cause disease. These data take advantage of genome sequencing projects and will use new powerful high throughput technologies. Gathering these data will be important for developing new treatments that will prevent T. gondii from persisting in infected people, and understanding how Apicomplexan parasites cause disease.

描述（由申请人提供）：本申请侧重于顶复门，这是发展中国家许多疾病的病原体，与全球健康有关（主题领域4）。它使用基因组学和其他高通量技术（主题领域1），对大型数据集进行系统级集成，分析和挖掘，其总体目标是将我们的发现转化为治疗和疾病预防的新见解（主题领域2）。为了实现我们的目标，我们组建了一个多学科合作团队，拥有传染病，糖尿病，代谢，病理学，分子生物学，动物模型和病理生理学方面的专业知识，在具有挑战性的生物医学领域（主题领域5）进行创新研究。顶复门寄生虫作为主要的新出现和重新出现的病原体，感染了世界上三分之一以上的人口。这些专性细胞内寄生虫包括刚地弓形虫、疟原虫属和隐孢子虫。弓形虫是艾滋病流行病的主要机会致病菌，是出生缺陷的原因，也是B类优先病原体，因为它与水传播疾病爆发有关。疟原虫是疟疾的病原体，每年感染2.67亿多人，每年造成近100万人死亡。尽管这些寄生虫在人类疾病中的重要性，但对于这些病原体没有有效的疫苗，并且需要新的治疗和预防疾病的策略。很少有人知道顶复门是如何调节毒力性状和应对环境变化的。新的高通量技术的发展使得能够收集大的基因组学和蛋白质组学数据集。这些可以用来发展一个完整的了解真核细胞如何调节基因表达。我们将利用基因组操作，全基因组阵列，高通量测序和蛋白质组学开发的数据集，这将有利于一个综合的系统方法来理解调节基因表达和表观遗传学的模型apicomplexan T. gondii。我们将测试的必要性，染色质重塑和候选转录因子使用一个适度的吞吐量基因破坏策略。使用表位标记的染色质重塑和转录因子，我们将使用染色质免疫沉淀物和表达微阵列的高通量测序来识别共调控基因组。最后，我们将进行高通量蛋白质组学，以表征参与基因表达调控的大分子复合物的成分。这些表观基因组，转录组和蛋白质组数据集将有助于计算方法来模拟表观遗传和遗传因素在Apicomplexa基因网络内的相互作用。这一努力将创造重要的社区资源，使系统生物学的方法对理解的毒力性状的表达和确定新的药物靶标顶复门寄生虫。 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个体（包括艾滋病患者）的严重疾病，导致出生缺陷，由于其与水传播疾病爆发有关，因此属于生物防御类B病原体。最后，它是其他寄生虫（如导致人类疟疾的疟原虫）的模型系统。这些寄生虫影响了世界上三分之一以上的人口。我们正试图生成大型数据集，以帮助我们了解这些寄生病原体如何响应与人类宿主的相互作用，以及它们如何调节导致疾病的基因。这些数据利用了基因组测序项目，并将使用新的强大的高通量技术。收集这些数据对于开发新的治疗方法，防止T。弓形虫在感染人群中的持续存在，以及了解顶复门寄生虫如何引起疾病。