GCN5-mediated transcription in AIDS pathogen Toxoplasma
艾滋病病原体弓形虫中 GCN5 介导的转录
基本信息
- 批准号:7806539
- 负责人:
- 金额:$ 38.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-05-01 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS-Related Opportunistic InfectionsAcetylationAcquired Immunodeficiency SyndromeAcuteAffinityAffinity ChromatographyAutomobile DrivingAwardBindingCategoriesChronicCo-ImmunoprecipitationsCommunicable DiseasesComplexCoupledCystDNA BindingDNA Binding DomainDNA-Binding ProteinsDataDevelopmentDevelopmental GeneDevelopmental ProcessDiseaseDisease ProgressionDrug DesignElementsEukaryotaExhibitsFamilyFollow-Up StudiesFundingGene ExpressionGene Expression RegulationGene TargetingGenesGeneticGenetic TranscriptionGenomeGoalsHistone AcetylationHistone H3ImmunityImmunocompromised HostImmunosuppressionImpairmentInfectionInterventionKnock-outKnowledgeLeadLearningLettersLinkMediatingMicroarray AnalysisModificationMolecularNational Institute of Allergy and Infectious DiseaseOpportunistic InfectionsParasitesPathogenesisPathway interactionsPatientsPlayProbabilityProcessProtein BindingProteinsReagentRecruitment ActivityRegulator GenesResearchRiskRoleStagingStressTechniquesTestingTherapeutic InterventionTissuesToxoplasmaToxoplasma gondiiToxoplasmosisTranscription factor genesTransgenic OrganismsTranslatingWorkYeastsbiodefensecombatfightinghistone acetyltransferasehistone modificationinnovationknockout genemouse modelmutantnovelpathogenpreventpromoterpublic health relevanceresponsetranscription factoryeast two hybrid system
项目摘要
DESCRIPTION (provided by applicant): Toxoplasma gondii is a protozoan parasite that poses a significant risk to AIDS patients and is listed by NIAID as a Category B Priority Pathogen for biodefense. Fundamental to the pathogenic process is the ability of the parasite to develop into a latent tissue cyst that can re-emerge as a rapidly growing form upon impairment of immunity. Increased understanding of this developmental process will provide new opportunities for therapeutic intervention. The work in our first award period focused on GCN5 histone acetyltransferases (HATs) and led to the discovery that histone acetylation correlates with gene expression pertinent to Toxoplasma development. We have taken genetic approaches to define the roles of two distinct GCN5-family HATs we have characterized in Toxoplasma (TgGCN5-A and -B). We have found that the loss of TgGCN5 impairs the ability of Toxoplasma to up-regulate key developmentally expressed genes. We have also determined that some of the proteins interacting with TgGCN5 in a yeast two-hybrid screen have domains typical of transcriptional regulators; this is significant because the lack of DNA-binding transcription factors detectable in the Toxoplasma genome has hampered efforts to understand how gene expression is regulated. How Toxoplasma regulates transcription to grow effectively during the acute stage, and develop into a latent cyst during stress, represent major gaps in our knowledge that hinder our ability to fight the opportunistic infection. The data generated by the first award allow us to focus this renewal on defining mechanisms of GCN5- mediated gene regulation in the context of parasite development, which underlies pathogenesis. We hypothesize that the TgGCN5 HATs play key roles in Toxoplasma pathogenesis by forming distinct complexes with novel proteins that regulate developmental gene expression. Our specific aims include (1) Determine the roles of TgGCN5 HATs in pathogenesis; (2) Elucidate differences in TgGCN5 complexes during Toxoplasma development; (3) Define the mechanism by which each TgGCN5 is recruited to target gene promoters to coordinate developmental gene expression. The proposed research capitalizes on the novel reagents, techniques, and transgenic parasites that we have developed. The data generated will illuminate the mechanism behind developmental transitions in Toxoplasma that are responsible for disease progression, thus exposing novel points of therapeutic intervention. PUBLIC HEALTH RELEVANCE: Toxoplasma gondii is a protozoan parasite that causes significant disease as an opportunistic infection of AIDS patients. Chronic toxoplasmosis is currently incurable because the parasite is able to develop into cysts that remain latent until immunosuppression. The mechanisms driving the development of these cysts are the focus of our studies, as learning how Toxoplasma develops will identify novel points of therapeutic intervention. We are taking an innovative approach to use transcriptional regulators as a means to elucidate the mechanisms of parasite development. The regulation of gene expression plays a key role in this pathogenic process; therefore, our results stand a high probability of translating into useful new therapies to combat opportunistic infectious diseases like Toxoplasma.
描述(由申请人提供):弓形虫是一种原生动物寄生虫,对艾滋病患者构成重大风险,被 NIAID 列为生物防御的 B 类优先病原体。致病过程的基础是寄生虫发展成潜伏组织囊肿的能力,当免疫力受损时,这种囊肿可以以快速生长的形式重新出现。加深对这一发育过程的了解将为治疗干预提供新的机会。我们第一个奖励期的工作重点是 GCN5 组蛋白乙酰转移酶 (HAT),并发现组蛋白乙酰化与弓形虫发育相关的基因表达相关。我们采用遗传学方法来定义我们在弓形虫中表征的两个不同的 GCN5 家族 HAT(TgGCN5-A 和 -B)的作用。我们发现 TgGCN5 的缺失会损害弓形虫上调关键发育表达基因的能力。我们还确定,在酵母双杂交筛选中与 TgGCN5 相互作用的一些蛋白质具有典型的转录调节因子结构域;这一点意义重大,因为弓形虫基因组中缺乏可检测到的 DNA 结合转录因子,这阻碍了了解基因表达如何调控的努力。弓形虫如何调节转录以在急性阶段有效生长,并在应激期间发展成潜伏囊肿,代表了我们知识中的主要空白,阻碍了我们对抗机会性感染的能力。第一个奖项产生的数据使我们能够将这一更新的重点放在寄生虫发育背景下 GCN5 介导的基因调控的定义机制上,这是发病机制的基础。我们假设 TgGCN5 HAT 通过与调节发育基因表达的新型蛋白质形成独特的复合物,在弓形虫发病机制中发挥关键作用。我们的具体目标包括(1)确定TgGCN5 HAT在发病机制中的作用; (2) 阐明弓形虫发育过程中TgGCN5复合物的差异; (3) 定义每个 TgGCN5 被招募到目标基因启动子以协调发育基因表达的机制。拟议的研究利用了我们开发的新试剂、技术和转基因寄生虫。生成的数据将阐明导致疾病进展的弓形虫发育转变背后的机制,从而揭示治疗干预的新点。公共卫生相关性:弓形虫是一种原生动物寄生虫,可引起艾滋病患者的机会性感染,导致严重疾病。慢性弓形虫病目前无法治愈,因为寄生虫能够发育成包囊,并在免疫抑制之前保持潜伏状态。驱动这些囊肿发展的机制是我们研究的重点,因为了解弓形虫如何发展将确定治疗干预的新点。我们正在采取一种创新方法,使用转录调节因子作为阐明寄生虫发育机制的手段。基因表达的调控在这一致病过程中发挥着关键作用。因此,我们的结果很有可能转化为有用的新疗法来对抗弓形虫等机会性传染病。
项目成果
期刊论文数量(0)
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William J Sullivan其他文献
William J Sullivan的其他文献
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