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
基本信息
- 批准号:8048844
- 负责人:
- 金额:$ 563.02万
- 依托单位:
- 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:2010-09-30 至 2013-09-29
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAffectAnimal ModelApicomplexaAreaBindingBiological ModelsC-terminalCategoriesCessation of lifeChromatinCloningCollectionCommunicable DiseasesCommunitiesComplementary DNAComplexCongenital AbnormalityCryptosporidiumDNA BindingDNA Binding DomainDataData SetDevelopmentDiabetes MellitusDiseaseDisease OutbreaksDrug Delivery SystemsEnvironmentEpidemicEpigenetic ProcessEpitopesEssential GenesEukaryotic CellFunctional disorderGene ActivationGene ExpressionGene Expression ProfileGene Expression RegulationGenesGeneticGenomeGenomicsGoalsHumanImmunocompromised HostIndividualKnock-outLigationMacromolecular ComplexesMalariaMedicalMetabolismMiningModelingMolecular BiologyParasitesPathologyPlasmodiumPopulationProtein BindingProteinsProteomicsPublic HealthResourcesSpecificitySystemSystems BiologyTestingToxoplasmaToxoplasma gondiiTranscription factor genesTranslatingVaccinesVirulencebasebiodefensecombinatorialdisorder preventionepigenomicsexpression vectorgenome sequencinggenome-wideglobal healthhigh throughput technologyhuman diseaseinnovationinsightmultidisciplinarynovelobligate intracellular parasitepathogenpreventprotein expressionpublic health relevanceresponsetraittranscription factortreatment strategywaterborne
项目摘要
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):本申请的重点是发展中国家许多疾病的APICOMPLEXA,病因学剂,与全球健康有关(主题4)。它使用基因组学和其他高吞吐量技术(主题区域1)以及对大型数据集进行系统级集成,分析和采矿,其总体目标是将我们的发现转化为新的见解和预防疾病的新见解(主题区域2)。为了实现我们的目标,我们组建了一个具有传染病,糖尿病,新陈代谢,病理学,分子生物学,动物模型和病理生理学的多学科合作团队,以在挑战性的生物医学领域进行创新研究(Thematic Pareation 5)。随着主要的新兴病原体和重新出现的病原体,Apicomplexan寄生虫感染了世界人口的三分之一。这些强制性细胞内寄生虫包括弓形虫,疟原虫和隐孢子虫。弓形虫Gondii是艾滋病流行病的主要机会病原体,这是出生缺陷的原因,由于其与水源性疫情的关联,也是B类优先剂。疟疾药物疟原虫每年感染超过2.67亿人,每年造成近100万人死亡。尽管这些寄生虫在人类疾病中很重要,但对于这些病原体,尚无有效的疫苗,需要新的治疗和预防疾病的策略。几乎没有理解的是,Apicomplexa如何调节毒力特征并应对其环境变化。新的高通量技术的开发使大型基因组和蛋白质组学数据集的收集。这些可用于发展对真核细胞如何调节基因表达的综合理解。我们将利用基因组操纵,全基因组阵列,高吞吐量测序和蛋白质组学来开发数据集,这些数据集将促进集成系统方法,以了解模型Apicomplexan T.Gondii中基因表达和表观遗传学的调节。我们将使用适度的贯穿基因破坏策略来测试染色质重塑器和候选转录因子的重要性。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吞吐量测序来识别共同调节的基因组。最后,我们将执行高通量蛋白质组学来表征与基因表达调节有关的大分子复合物的成分。这些表观基因组,转录组和蛋白质组学数据集将促进计算方法,以模拟APICOMPLEXA中的表观遗传学和遗传因素如何在基因网络中相互作用。这项工作将创造重要的社区资源,以使系统生物学方法能够理解毒力性状的表达以及对Apicomplexan寄生虫的新药物靶标的识别。
公共卫生相关性:弓形虫Gondii是一种寄生虫病原体,在包括艾滋病患者在内的免疫功能低下的个体中引起严重疾病,导致先天缺陷,并且由于其与水生爆发的关联而是生物衰落的B类病原体。最后,它是导致人类疟疾的其他寄生虫等其他寄生虫的模型系统。这些寄生虫影响了世界人口的三分之一。我们正在尝试生成大型数据集,以帮助我们了解这些寄生病原体如何因与人类宿主的相互作用以及它们如何调节引起疾病的基因而发生变化。这些数据利用了基因组测序项目,并将使用新的强大高通量技术。收集这些数据对于开发新的治疗方法将很重要,以防止贡迪(T. gondii)持续受感染者的持续存在,并了解Apicomplexan寄生虫如何引起疾病。
项目成果
期刊论文数量(0)
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Kami Kim其他文献
Kami Kim的其他文献
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{{ truncateString('Kami Kim', 18)}}的其他基金
Dissecting the roles of protein O-GlcNAcylation in Toxoplasma gondii
剖析蛋白 O-GlcNAc 酰化在弓形虫中的作用
- 批准号:
8512340 - 财政年份:2013
- 资助金额:
$ 563.02万 - 项目类别:
Dissecting the roles of protein O-GlcNAcylation in Toxoplasma gondii
剖析蛋白 O-GlcNAc 酰化在弓形虫中的作用
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8719923 - 财政年份:2013
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$ 563.02万 - 项目类别:
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