A transmembrane Rab GTPase accelerating protein targeted to peroxisomes
一种针对过氧化物酶体的跨膜 Rab GTP 酶加速蛋白
基本信息
- 批准号:10595549
- 负责人:
- 金额:$ 14.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccelerationAddressAffinityAllelesAreaAutophagocytosisBindingBiochemicalBiological AssayCardiovascular DiseasesCardiovascular systemCellsCellular biologyClientCoupledCritical PathwaysDevelopmentDiseaseDockingEndoplasmic ReticulumEnzymesEukaryotic CellExerciseFamilyFluorescence MicroscopyGTP BindingGenesGoalsGolgi ApparatusGrowthGuanosine Triphosphate PhosphohydrolasesHealthHumanImaging TechniquesIntegral Membrane ProteinKineticsLipidsMaintenanceMapsMass Spectrum AnalysisMembraneMembrane FusionMetabolic DiseasesMetabolic PathwayMetabolismMicroscopicMitochondriaMitochondrial Membrane ProteinMolecularMolecular ChaperonesMorphologyMutagensMutationNerve DegenerationNeurodegenerative DisordersOrganellesOrganismOrthologous GeneOutcomes ResearchPathway interactionsPhenotypePlayProcessProteinsProteomicsQuality ControlRegulationReportingResearchResourcesRoleSaccharomyces cerevisiaeSignal TransductionSignaling ProteinSourceStimulusStressSynthetic GenesSystems BiologyTechnologyTestingTherapeutic InterventionTimeToxic effectTransmembrane TransportVesicleYeastsage relatedbiological adaptation to stresselectron tomographyin vivoinnovationlipid metabolismmembrane biogenesisperoxisomepreventprogramsrab GTP-Binding Proteinsrepairedresponsespatiotemporaltargeted treatmentvesicle transportyeast genome
项目摘要
Project Summary
Understanding how cells adapt to stress and repair damage is one of the highest priorities in cell biology and
health research. The endoplasmic reticulum (ER) is a key source of lipid and proteins for building and
maintaining several organelles in cells, and in response to stimuli it is capable of directing resources into an
assortment of transport pathways. The signaling protein Ypt1/Rab1 is a Rab GTPase (Rab) that plays
essential roles in how the ER directs resources and executes quality control of damaged organelles including
mitochondria and peroxisomes. Our long-term goal is to understand the mechanisms for how lipid and protein
cargos are routed and re-routed to specific itineraries in response to cellular stimuli and stresses, which will
inform development of targeted therapeutic interventions to address diseases. We have found that the
GTPase accelerating protein Gyp8, an evolutionarily conserved but poorly understood negative regulator of
Ypt1/Rab1 signaling, localizes to the ER, peroxisomes and mitochondria and impinges on Ypt1 signaling. Our
central hypotheses are that Gyp8 functions to modulate Ypt1/Rab1 signaling in the early secretory pathway
(ER) and at non-secretory membranes (peroxisomes and mitochondria) that are subject to frequent damage
and quality control via Ypt1/Rab1-dependent selective autophagy. Also, since Gyp8 localizes to organelles
that commonly tether/dock to exchange materials in essential metabolic pathways, we predict that Gyp8
regulates Rab-dependent tethering interactions, particularly among organelles specialized for lipid storage and
metabolism. To test our central hypotheses and advance understanding of several membrane biogenesis
pathways that originate at the ER, we will pursue these specific aims: 1) Identify intra- and extra-genic factors
that control the subcellular itinerary and activity of Gyp8; 2) Determine target Rab GTPase(s) regulated by
Gyp8 in the secretory pathway; and 3) Define the role of Gyp8 in regulating peroxisomal and mitochondrial
dynamics. The proposed research is innovative both for area of focus and technical approach. While
Ypt1/Rab1 signaling controls multiple transport pathways essential to cellular health, understanding of where
and when signal must be terminated to accomplish each of its roles is particularly incomplete. The
experimental plan combines gold standard biochemical and imaging techniques in organelle and vesicular
transport (enzyme-coupled kinetic transport assays and 3D electron tomography) with systems biology
approaches (synthetic gene array and affinity capture mass spectrometry proteomics). The proposed research
is significant because defining how Ypt1/Rab1 is regulated to support and exercise quality control of ER,
mitochondria and peroxisomes is foundational to understanding aspects of cardiovascular, neurodegenerative
and metabolic disorders.
项目摘要
了解细胞如何适应压力和修复损伤是细胞生物学和
健康研究。内质网(ER)是建筑物和蛋白质的关键来源
保持细胞中的几个细胞器,并在响应刺激中,能够将资源引导到一个
各种运输途径。信号蛋白ypt1/rab1是播放的Rab GTPase(RAB)
急诊室如何指导资源和执行受损细胞器的质量控制在内的重要作用
线粒体和过氧化物酶体。我们的长期目标是了解脂质和蛋白质的机制
响应细胞刺激和应力,将货物路由并重新列为特定的行程,这将
告知有针对性的治疗干预措施以解决疾病。我们发现
GTPase加速蛋白GYP8,这是一种进化保守但知之甚少的负调节剂
YPT1/RAB1信号传导,位于ER,过氧化物酶体和线粒体,并影响YPT1信号传导。我们的
中心假设是GYP8在早期分泌途径中调节YPT1/RAB1信号的功能
(ER)和在非分泌膜(过氧化物酶体和线粒体)处受到频繁损害
和质量控制通过YPT1/RAB1依赖性选择性自噬。另外,由于GYP8本地化为细胞器
通常是在基本代谢途径中交换材料的系绳/码头,我们预测GYP8
调节RAB依赖性的绑扎相互作用,尤其是在专门用于脂质存储和的细胞器中
代谢。测试我们的中心假设并提高对几种膜生物发生的理解
起源于急诊室的途径,我们将追求这些特定目的:1)确定内部和外部因素
控制GYP8的亚细胞行程和活性; 2)确定由
GYP8在分泌途径中; 3)定义GYP8在调节过氧化物酶体和线粒体中的作用
动力学。拟议的研究对于重点领域和技术方法都是创新的。尽管
YPT1/RAB1信号控制蜂窝健康必不可少的多个传输途径
当必须终止信号以完成其每个角色时,特别是不完整的。这
实验计划结合了细胞器和水泡中的金标准生化和成像技术
传输(酶耦合动力学传输测定和3D电子断层扫描)与系统生物学
方法(合成基因阵列和亲和力捕获质谱蛋白质组学)。拟议的研究
之所以重要,是因为定义如何调节YPT1/RAB1以支持和行使ER的质量控制,
线粒体和过氧化物酶体是理解心血管,神经退行性方面的基础
和代谢障碍。
项目成果
期刊论文数量(1)
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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Daniel P. Nickerson其他文献
Daniel P. Nickerson的其他文献
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{{ truncateString('Daniel P. Nickerson', 18)}}的其他基金
A transmembrane Rab GTPase accelerating protein targeted to peroxisomes
一种针对过氧化物酶体的跨膜 Rab GTP 酶加速蛋白
- 批准号:
10398972 - 财政年份:2021
- 资助金额:
$ 14.7万 - 项目类别:
A transmembrane Rab GTPase accelerating protein targeted to peroxisomes
一种针对过氧化物酶体的跨膜 Rab GTP 酶加速蛋白
- 批准号:
10172761 - 财政年份:2021
- 资助金额:
$ 14.7万 - 项目类别:
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