Functional Analysis of Novel Components of the Toxoplasma Inner Membrane Complex
弓形虫内膜复合物新成分的功能分析
基本信息
- 批准号:9384311
- 负责人:
- 金额:$ 37.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsApicalBiologyBiotinBiotinylationCRISPR screenCell membraneCellsCellular biologyCharacteristicsCoccidiosisComplexConeCytoskeletal FilamentsCytoskeletonDaughterDiseaseEimeria tenellaElementsEventFalciparum MalariaFamilyHumanImmobilizationIn VitroInfectionInvadedKnock-outKnowledgeLeadLigaseMass Spectrum AnalysisMediatingMedicalMembraneMethodsMicrotubulesMorphologyMotorNamesNeospora caninumOrganellesParasitesPeripheralPlayProcessProteinsProteomeReportingRoleSeriesShapesStreptavidinSurgical suturesSystemTimeLineToxoplasmaToxoplasma gondiiToxoplasmosisVesicleVirulenceXenopus oocytecell motilitycholine transportercohortdaughter celldesignexperimental studyfitnessgenome-widein vivoinsightmembermembrane biogenesisnovelnovel therapeuticsobligate intracellular parasiteparasite invasionpathogenprotein complexprotein functionscaffold
项目摘要
PROJECT SUMMARY
Toxoplasma gondii and related apicomplexan parasites contain a specialized organelle called the inner
membrane complex (IMC) that plays essential roles in host cell invasion and daughter cell formation.
Determining the precise functions of the IMC has been hampered by a limited understanding of its protein
constituents, which have predominantly focused on the motor components of the glideosome that powers
parasite motility and the family of alveolins that are embedded within the IMC cytoskeletal network underlying
the flattened membrane vesicles of the organelle. We have recently overcome this gap in our knowledge using
in vivo biotinylation (BioID) to identify over forty new IMC components, more than doubling the known IMC
proteome. These new proteins have revealed a surprising level of compartmentalization within the organelle,
with distinct components segregating to the cytoskeletal or membrane subregions of the apical cap, IMC body,
or the recently discovered IMC sutures, which organize the IMC membranes into their characteristic
rectangular plates. Analyses of a few of these proteins have revealed new important roles in controlling
parasite shape, cellular division, and invasion. In this proposal, we will leverage our new cohort of IMC proteins
to first provide a temporal and spatial understanding of how these components participate in the dynamic
process of internal budding known as endodyogeny. This will reveal groups of proteins that function to
assemble the IMC at specific steps of endodyogeny and also provide insight into the dynamic process of
distinguishing maternal and daughter IMCs during division. We will then explore how the key IMC suture
proteins ISC3 and ISC6 regulate proper IMC membrane biogenesis, parasite morphology and replication.
Finally, we exploit the recent genome-wide CRISPR screen in Toxoplasma to focus on a subset of our new
IMC proteins that are likely to play crucial roles within distinct suborganellar compartments of the organelle.
Together, this project will fundamentally transform our understanding of the organization and function of the
Toxoplasma IMC. As this organelle is parasite-specific and is not present in its human host, elucidating critical
IMC components and their respective functions promises to reveal ideal targets for the design of novel
therapies against T. gondii and other apicomplexan parasites.
项目总结
弓形虫和相关的顶端复合体寄生虫含有一种特殊的细胞器,称为内细胞器
膜复合体(IMC),在宿主细胞入侵和子代细胞形成中起重要作用。
由于对IMC蛋白质的了解有限,IMC的精确功能一直受到阻碍
主要集中在为胶质小体提供动力的运动组件上
寄生虫的运动性和嵌入IMC细胞骨架网络的肺泡蛋白家族
细胞器的扁平的膜小泡。我们最近用我们的知识克服了这一鸿沟
体内生物素化(BioID)识别40多个新的IMC成分,是已知IMC的两倍多
蛋白质组。这些新蛋白质揭示了细胞器内令人惊讶的区隔程度,
不同的成分分离到顶帽的细胞骨架或膜亚区,IMC小体,
或者是最近发现的IMC缝合线,它将IMC膜组织成它们的特征
矩形板材。对其中几种蛋白质的分析揭示了新的重要调控作用
寄生虫的形状、细胞分裂和入侵。在这项提案中,我们将利用我们新的IMC蛋白质队列
首先提供对这些组件如何参与动态的时空理解
内部萌发的过程称为内生作用。这将揭示一组蛋白质,它们的功能是
在内生的特定步骤组装IMC,并提供对
在分裂过程中区分母女IMC。然后我们将探索关键的IMC缝合是如何
ISC3和ISC6蛋白调节适当的IMC膜生物发生、寄生虫的形态和复制。
最后,我们利用最近在弓形虫基因组范围内的CRISPR屏幕来关注我们新的
IMC蛋白可能在细胞器不同的亚细胞器隔间中发挥关键作用。
总而言之,这个项目将从根本上改变我们对世界银行组织和职能的理解
弓形虫IMC。由于这种细胞器是寄生虫特有的,不存在于其人类宿主中,因此阐明了关键
IMC组件及其各自的功能有望为小说的设计揭示理想的目标
针对弓形虫和其他尖端复合体寄生虫的治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Peter John Bradley其他文献
Peter John Bradley的其他文献
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{{ truncateString('Peter John Bradley', 18)}}的其他基金
Functional Analysis of Novel Components of the Toxoplasma Inner Membrane Complex
弓形虫内膜复合物新成分的功能分析
- 批准号:
9533992 - 财政年份:2017
- 资助金额:
$ 37.89万 - 项目类别:
Functional Analysis of Novel Components of the Toxoplasma Inner Membrane Complex
弓形虫内膜复合物新成分的功能分析
- 批准号:
10444432 - 财政年份:2017
- 资助金额:
$ 37.89万 - 项目类别:
Functional Analysis of Novel Components of the Toxoplasma Inner Membrane Complex
弓形虫内膜复合物新成分的功能分析
- 批准号:
10550156 - 财政年份:2017
- 资助金额:
$ 37.89万 - 项目类别:
Novel Dense Granule Protein Function in the Chronic Toxoplasma Infection
慢性弓形虫感染中的新型致密颗粒蛋白功能
- 批准号:
9221240 - 财政年份:2016
- 资助金额:
$ 37.89万 - 项目类别:
Novel Dense Granule Protein Function in the Chronic Toxoplasma Infection
慢性弓形虫感染中的新型致密颗粒蛋白功能
- 批准号:
9141001 - 财政年份:2016
- 资助金额:
$ 37.89万 - 项目类别:
Reconstitution of Plasmodium Export in Toxoplasma
弓形虫中疟原虫输出的重建
- 批准号:
8463994 - 财政年份:2012
- 资助金额:
$ 37.89万 - 项目类别:
Novel rhoptry effector proteins in Toxoplasma host-pathogen interaction
弓形虫宿主-病原体相互作用中的新型棒状体效应蛋白
- 批准号:
8229898 - 财政年份:2012
- 资助金额:
$ 37.89万 - 项目类别:
Reconstitution of Plasmodium Export in Toxoplasma
弓形虫中疟原虫输出的重建
- 批准号:
8356983 - 财政年份:2012
- 资助金额:
$ 37.89万 - 项目类别:
Novel rhoptry effector proteins in Toxoplasma host-pathogen interaction
弓形虫宿主-病原体相互作用中的新型棒状体效应蛋白
- 批准号:
8416941 - 财政年份:2012
- 资助金额:
$ 37.89万 - 项目类别:
The Role of Toxoplasma Rhoptries in Host Cell Infection
弓形虫在宿主细胞感染中的作用
- 批准号:
7153481 - 财政年份:2005
- 资助金额:
$ 37.89万 - 项目类别:
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