Investigating the role of AAA+-ATPases in peroxisome biology
研究 AAA -ATP 酶在过氧化物酶体生物学中的作用
基本信息
- 批准号:10001560
- 负责人:
- 金额:$ 24.9万
- 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:2017-05-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAdaptor Signaling ProteinArchitectureAutophagocytosisBile AcidsBiochemicalBiochemical GeneticsBiochemistryBiogenesisBiological AssayBiologyBrainCellsComplexCryoelectron MicroscopyCrystallizationCytosolDefectDevelopmentDiseaseDissectionElectron MicroscopyEncapsulatedEndoplasmic ReticulumEnvironmentEnzymesEukaryotaFluorescence MicroscopyFunctional disorderGenesGoalsGrowthHealthHomeostasisHumanHydrogen PeroxideIn VitroKnowledgeLipidsLiver DysfunctionLongevityMaintenanceMass Spectrum AnalysisMembraneMembrane BiologyMembrane Protein TrafficMembrane ProteinsMentorsMentorshipMetabolicMetabolismMicroscopyMitochondriaModelingMolecularMotorMutateMutationMyelin SheathNerve DegenerationOrganellesPHEX proteinPhenotypePlayProcessProtein ImportProteinsQuality ControlReactionRegulationResearchResourcesRoleSNAP receptorStructureSyndromeSystemTechniquesTestingTherapeutic InterventionTrainingTranslatingVery Long Chain Fatty Aciddevelopmental diseasedisease-causing mutationeffective therapyfascinatehigh throughput screeningimprovednovelnovel therapeutic interventionnovel therapeuticsperoxisomeperoxisome membraneprogramsreceptorreconstitutionresponseskillstrafficking
项目摘要
Project Summary: Peroxisomes are ubiquitous, membrane-bound organelles that encapsulate specialized
metabolic reactions, typically including those that produce hydrogen peroxide as a byproduct. In humans,
where peroxisomes breakdown very long chain fatty acids and synthesize precursors of bile acids and myelin
sheath lipids, defects in peroxisomes cause Peroxisome Biogenesis Disorders (PBDs), characterized by
neuronal degeneration, liver dysfunction, and decreased lifespan. There are currently no treatments for PBDs,
and our understanding of peroxisomes in human health is hindered by our limited understanding of the
biochemical mechanisms of peroxisome molecular membrane biology.
De novo biogenesis of peroxisomes requires approximately 30 dedicated Pex proteins. During this
process, the peroxisome membrane and membrane proteins traffic through the endoplasmic reticulum, while
the matrix proteins are imported fully folded from the cytosol. The majority of PBDs are caused by mutations in
Pex1 and Pex6, two AAA+-ATPase motor proteins that perform an uncharacterized task crucial for peroxisome
matrix protein import. A complete understanding of Pex1 and Pex6 architecture, substrates, processing
mechanism, and function at the peroxisome would reveal new mechanistic details of peroxisome formation,
novel therapeutic strategies, and expand our understanding of the role of peroxisomes in disease.
As a Miller Fellow in Dr. Andreas Martin's lab, I used in vitro biochemistry and electron microscopy to
determine the architecture of the active Pex1/Pex6 complex and its interaction and regulation by its membrane
tether protein Pex15. This represents the first structural and biochemical characterization of Pex1/Pex6 and a
unique molecular handle to dissect the energy-dependent steps of peroxisome assembly. In this proposal I will
expand my research to understand the function of Pex1/Pex6 in the context of the cell and peroxisome
dysfunction in the context of cellular homeostasis. In Aim 1, with the mentorship of Dr. Martin, an expert on
AAA+-ATPase mechanisms, I propose to identify the substrates of Pex1/Pex6 and determine their processing
mechanism. In Aim 2, with mentorship from Dr. Schekman, an expert in biochemical dissections of membrane
trafficking, I will determine Pex1/Pex6 function in peroxisome matrix protein import using a novel cell-free
reconstitution. Finally, I propose to determine the cellular response to induced peroxisome dysfunction and
identify novel proteins required for peroxisome maintenance.
With the support of my mentors and the greater research environment at UC Berkeley, I will receive
training in mass spectrometry, cryo-electron microscopy, cell-free reconstitutions, fluorescence microscopy,
and high throughput screening. These skills will help me bridge my background in biochemistry with my
fascination with organelle biology to build a successful independent research program investigating the
biochemical mechanisms of peroxisome biology.
项目概述:过氧化物酶体是一种普遍存在的膜结合细胞器
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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Brooke Meghan Gardner其他文献
Brooke Meghan Gardner的其他文献
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{{ truncateString('Brooke Meghan Gardner', 18)}}的其他基金
Investigating the mechanisms of peroxisome homeostasis
研究过氧化物酶体稳态机制
- 批准号:
10680467 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Investigating the mechanisms of peroxisome homeostasis
研究过氧化物酶体稳态机制
- 批准号:
10808484 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Investigating the role of AAA+-ATPases in peroxisome biology
研究 AAA -ATP 酶在过氧化物酶体生物学中的作用
- 批准号:
10245266 - 财政年份:2017
- 资助金额:
$ 24.9万 - 项目类别: