Dissecting new mechanisms of lysosome quality control in health and disease
剖析健康和疾病中溶酶体质量控制的新机制
基本信息
- 批准号:10594038
- 负责人:
- 金额:$ 36.2万
- 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:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcuteAffinityAgingArchitectureAutophagocytosisBindingBiochemicalBiochemistryBiogenesisBiological AssayC-terminalC2 DomainCalciumCatabolismCell Membrane PermeabilityCell ProliferationCell membraneCell physiologyCellsCharacteristicsChemicalsCoupledCytoplasmDYSF geneDataDedicationsDefectDegenerative DisorderDependenceDigestionDiseaseDisease ProgressionDissectionEndowmentEnsureFamilyFamily memberFluorescent ProbesGoalsGolgi ApparatusGrowthHealthHomeostasisImpairmentIn VitroLipid BilayersLysosomesMaintenanceMalignant NeoplasmsMalignant neoplasm of pancreasMass Spectrum AnalysisMeasurementMeasuresMechanical StressMediatingMembraneMembrane ProteinsMetabolicMetabolismMitochondriaMorphologyMuscular DystrophiesMutationMyoblastsNormal CellNutrientOrganellesPancreatic Ductal AdenocarcinomaPathogenesisPathway interactionsPhospholipidsPhosphotransferasesProcessPropertyProtein FamilyProteinsProteomicsQuality ControlReactionRecyclingResistanceRoleRouteSignal TransductionSkeletal MuscleStressTestingTransmembrane Domaincell typecomparativecopingdetection of nutrientin vivoinsightlysosome membranemembermetabolomicsmutantnovelpancreatic ductal adenocarcinoma cellpreservationprogramsrepairedresilienceresponsesealtraffickingtranscription factortumor growth
项目摘要
PROJECT SUMMARY
Lysosomes function as critical nodes for macromolecular recycling, metabolic rewiring, and pro-growth
signaling in cells. Accordingly, defects in lysosome function underlie degenerative diseases and aging while
hyperactivation of lysosomes are associated with cancer. Prior studies have shown that highly aggressive
Pancreatic ductal adenocarcinoma (PDA) cells upregulate lysosome biogenesis and activity to facilitate
degradation, clearance and recycling of incoming cargo material delivered by increased rates of autophagy and
macropinocytosis. Whether qualitative differences endow PDA lysosomes with unique structural and functional
properties to cope with a higher demand for substrate clearance remains unknown. To answer this question, we
have conducted the first comparative proteomics analysis of lysosomes isolated from PDA versus normal cells
and have identified members of the Ferlin family of membrane repair factors, Myoferlin and Dysferlin, as
selectively enriched on the membrane of PDA lysosomes. We propose that Ferlin proteins confer
increased protection against lysosomal membrane stress in PDA cells.
Ferlin proteins are normally localized on the plasma membrane of cell types subjected to heightened
mechanical stress, such as skeletal muscle, where they facilitate repair of the lipid bilayer. Accordingly, mutations
in DYSF are associated with two forms of muscular dystrophy whereby impaired membrane resealing
compromises myoblast maturation, fusion and plasma membrane repair. Therefore, we hypothesize that PDA
cells hijack and repurpose Ferlin proteins at the lysosome membrane to protect the integrity of this organelle. In
support of this hypothesis, our preliminary findings show that PDA lysosomes are more resistant to acute
chemically induced membrane permeabilization relative to normal cells. Mechanistically, lysosome localization
of MYOF is necessary and sufficient for maintenance of lysosome quality control and its suppression leads to
profound defects in lysosome morphology, PDA cell proliferation and in vivo tumor growth. The goal of this
study is to investigate how MYOF functions to protect the lysosome membrane in mechanistic detail and to
determine the impact of blocking lysosome quality control on cellular metabolism, pro-growth signaling and
disease progression. In summary, our discovery and proposed studies will be the first to determine a novel
function for Ferlin proteins at the lysosome membrane and provide insight into how enhanced lysosome quality
control regulates cellular homeostasis and disease pathogenesis.
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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Rushika Miriam Perera其他文献
Rushika Miriam Perera的其他文献
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{{ truncateString('Rushika Miriam Perera', 18)}}的其他基金
Targeting the autophagy-lysosome system to block pancreatic cancer
靶向自噬溶酶体系统来阻止胰腺癌
- 批准号:
10212065 - 财政年份:2021
- 资助金额:
$ 36.2万 - 项目类别:
Targeting the autophagy-lysosome system to block pancreatic cancer
靶向自噬-溶酶体系统来阻止胰腺癌
- 批准号:
10358483 - 财政年份:2021
- 资助金额:
$ 36.2万 - 项目类别:
Targeting the autophagy-lysosome system to block pancreatic cancer
靶向自噬-溶酶体系统来阻止胰腺癌
- 批准号:
10590682 - 财政年份:2021
- 资助金额:
$ 36.2万 - 项目类别:
Dissecting new mechanisms of lysosome quality control in health and disease
剖析健康和疾病中溶酶体质量控制的新机制
- 批准号:
10186267 - 财政年份:2021
- 资助金额:
$ 36.2万 - 项目类别:
Dissecting new mechanisms of lysosome quality control in health and disease
剖析健康和疾病中溶酶体质量控制的新机制
- 批准号:
10370440 - 财政年份:2021
- 资助金额:
$ 36.2万 - 项目类别:
Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer
识别胰腺癌细胞可塑性的分子驱动因素
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10404053 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer
识别胰腺癌细胞可塑性的分子驱动因素
- 批准号:
10626914 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer
识别胰腺癌细胞可塑性的分子驱动因素
- 批准号:
10252885 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer
识别胰腺癌细胞可塑性的分子驱动因素
- 批准号:
9974205 - 财政年份:2020
- 资助金额:
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