Regulation of protein transport in cilia
纤毛中蛋白质运输的调节
基本信息
- 批准号:10116415
- 负责人:
- 金额:$ 31.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-06-10 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeAntibodiesBardet-Biedl SyndromeBindingBinding SitesBiochemicalBlindnessCarrier ProteinsCell membraneCellsChlamydomonasChlamydomonas reinhardtiiChronicCiliaComplexDataDefectDeteriorationDevelopmentDiffusionDiseaseEnsureFlagellaFluorescence Resonance Energy TransferFrequenciesGoalsHarvestHeterogeneityHumanImpairmentIn VitroInfectionJoubert syndromeLengthLipidsLiquid substanceMaintenanceMale InfertilityMapsMasksMembraneMembrane LipidsMembrane ProteinsMicrotubulesModelingModificationMonitorMotorMutationObesityOrganellesPathway interactionsPatternPerformancePhospholipase DPositioning AttributeProtein Export PathwayProtein ImportProtein PrecursorsProteinsRegulationResearchRibosomesRoleRouteSensorySignal TransductionStructural ProteinStructureTestingTimeTrainingTravelTubulinWorkbasecarbonate dehydratasecell motilityciliopathycilium biogenesisin vivoin vivo imaginginsightinterestmutantparticleprotein transporttool
项目摘要
Project Summary
Cilia and flagella are conserved microtubule-based cell extensions present on most cells in the
mammalian body. In addition to their role in cell locomotion and fluid transport, cilia participate in cellular
sensing and signaling. Over the past two decades, it has been established that numerous developmental
anomalies and diseases are caused by dysfunctional cilia. The goal of our work is to understand how
cells assemble and maintain cilia, which both require protein transfer between the cell body and the
organelle. A key mechanism that determines the protein content of cilia is intraflagellar transport (IFT), a
motor-based motility of large carriers (“IFT trains”) that move proteins in and out of cilia. We will use
Chlamydomonas reinhardtii as a unicellular model to determine how IFT identifies proteins destined for
the cilium and how the cells regulate the volume and timing of ciliary protein traffic. In Aim1, we will focus
on the transport of tubulin, the main structural protein of cilia and flagella. The amount of tubulin and
other axonemal proteins entering cilia on IFT trains is upregulated while cilia grow. Tubulin also enters
cilia by diffusion and we will establish the quantitative contribution of each route in cilia assembly. We will
determine if IFT54 is part of the previously characterized IFT74-IFT81 tubulin-binding module or if it
forms an independent tubulin-binding site. All three proteins interact with tubulin via their tubulin-binding
domains (TBDs). Isolated IFT complexes will be used to study if the TBDs undergo biochemical changes
related to cargo binding and cilia length. We will attempt to map the TBDs on isolated IFT particles and
we will study whether IFT particles undergo structural changes inside cilia potentially explaining the
differences in cargo binding. We expect to gain insights into how cells regulate tubulin transport, which is
critical for the timing of ciliogenesis and the regulation of ciliary length. In Aim 2, we will focus on the
transport of proteins associated to the ciliary membrane by lipidation. Such proteins are critical for the
sensory and signaling functions of cilia. Often, they enter and exit cilia to modulate signaling but the role
of IFT in this traffic is mostly unknown. In cilia of C. reinhardtii mutants in BBS proteins or Arl13b, the
patterns of membrane-associated proteins are severely affected. In humans, mutations in BBS proteins
and Arl13b result in Bardet-Biedl syndrome (BBS) and Joubert syndrome, respectively. Both mutants
show loss and abnormal accumulation of membrane-associated proteins in cilia, raising the question
whether more than one route of transport is affected. We will use in vivo imaging to determine the role of
IFT and diffusion in ciliary entry and export of proteins mislocalized in these mutants. We will test a
hypothesis that initial ciliary defects caused directly by the bbs and arl13b mutations will induce
additional biochemical defects increasingly impairing cilia over time.
项目总结
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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Karl Lechtreck其他文献
Karl Lechtreck的其他文献
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{{ truncateString('Karl Lechtreck', 18)}}的其他基金
Pattern formation and function of PKD2/polycystin-2 in motile cilia
运动纤毛中 PKD2/多囊蛋白-2 的模式形成和功能
- 批准号:
10096638 - 财政年份:2020
- 资助金额:
$ 31.5万 - 项目类别:
Pattern formation and function of PKD2/polycystin-2 in motile cilia
运动纤毛中 PKD2/多囊蛋白-2 的模式形成和功能
- 批准号:
10456237 - 财政年份:2020
- 资助金额:
$ 31.5万 - 项目类别:
Pattern formation and function of PKD2/polycystin-2 in motile cilia
运动纤毛中 PKD2/多囊蛋白-2 的模式形成和功能
- 批准号:
10673124 - 财政年份:2020
- 资助金额:
$ 31.5万 - 项目类别:
Pattern formation and function of PKD2/polycystin-2 in motile cilia
运动纤毛中 PKD2/多囊蛋白-2 的模式形成和功能
- 批准号:
10266797 - 财政年份:2020
- 资助金额:
$ 31.5万 - 项目类别:
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