Apolipoprotein L1 Interaction with SNARE Proteins in the Pathogenesis of Chronic Kidney Disease
载脂蛋白 L1 与 SNARE 蛋白在慢性肾脏病发病机制中的相互作用
基本信息
- 批准号:10055541
- 负责人:
- 金额:$ 16.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:APOL1 geneAccountingAddressAffectAfricanAfrican AmericanAgeAmericanAmino Acid SequenceApolipoproteinsAttenuatedAutophagosomeBindingBiochemicalBiologicalBiological ModelsCell Culture TechniquesCell LineCellsCellular biologyChronic Kidney FailureCo-ImmunoprecipitationsConfocal MicroscopyCytoplasmCytoskeletonDataData AnalysesDefectDevelopmentDiagnosisDialysis procedureDiseaseDisease ProgressionEnd stage renal failureEventExpenditureFocal Segmental GlomerulosclerosisFollow-Up StudiesGenesGenetic Predisposition to DiseaseGenetic VariationGoalsGraft SurvivalHigh Density Lipoprotein CholesterolHumanImageImmuneImmune System DiseasesImmunofluorescence MicroscopyImmunologic FactorsImmunologic TestsIndividualInterferon Type IIInterleukin-1 betaInvestigationKidneyKidney DiseasesKidney FailureKnowledgeLeadLearningLocationMass Spectrum AnalysisMeasuresMediatingMedicareMembrane FusionMinorityModelingMolecularNMR SpectroscopyPathogenesisPathologicPathway interactionsPatientsPatternPhysiciansPhysiologicalPopulationPrevalencePreventionProtein ConformationProtein FamilyProteinsProteinuriaProteomicsPublic HealthPublishingRiskRoleSNAP receptorScientistSecondary toStimulusStructural ModelsStructureTNF geneTestingTimeTransgenic MiceUnited StatesVariantVesiclebasebioinformatics toolbiological adaptation to stressclinically significantcytotoxicitydesigndisease diagnosisexperimental studygenetic variantglomerulosclerosishuman imagingimmune activationin silicoknock-downlive cell imagingnon-diabeticnovel strategiesnovel therapeutic interventionpatient populationpodocytepublic health relevancerecruitresponserisk variantskillsstable cell linethree dimensional structuretooltrafficking
项目摘要
Summary
Chronic kidney diseases (CKDs) are a major public health problem affecting more than 20 million people in the
United States. African Americans are disproportionately affected by progressive CKDs, especially focal
segmental glomerulosclerosis (FSGS). Genetic variants in the carboxy-terminal domain of APOL1 are
associated with FSGS and other non-diabetic CKDs in populations with African ancestry. These variants change
the amino acid sequence of APOL1 and explain much of this increased risk for CKDs in these populations. The
pathogenetic mechanisms that lead from these APOL1 variants to CKD are not known. The carboxy-terminus of
APOL1 interacted with VAMP8, an endosomal/lysosomal SNARE protein involved in vesicular trafficking and
APOL1 kidney disease-associated variants attenuated the interaction with VAMP8 secondary to protein
conformational changes induced by the variants. Like SNARE proteins, APOL1 localized to vesicular structures
in the podocytes of the healthy human kidney. We hypothesize that APOL1:SNARE interaction is necessary to
mitigate/attenuate podocyte stress response, and APOL1 variants disrupt functional SNARE interaction and
mediate cytotoxicity.
To test this hypothesis, we propose the following aims:
First, we will use stable cell lines expressing APOL1 and healthy human kidneys to identify additional interacting
SNARE proteins. We will use live-cell confocal microscopy to track APOL1:SNARE localization in various
subcellular compartments in the presence and absence of immune stimuli.
Second, we will investigate the cytotoxicity of reference and variant APOL1 proteins in the absence and presence
of immune stimuli and reference APOL1 in the absence and presence of SNARE knockdown in cell culture
models.
Through these aims, I will obtain biochemical, imaging and proteomics data necessary to address our long term
goal of identifying agents for the treatment of APOL1-associated kidney diseases. Understanding the molecular
mechanisms by which APOL1 variants cause proteinuric CKD is essential for the development of new
therapeutic strategies. I propose to use imaging and proteomics tools to study the pathological effects of APOL1
variants on its function and to learn bioinformatics tools to allow me to develop models to investigate CKD
mechanisms. As a young physician-scientist, this project will help me to acquire new skills and knowledge while
studying an important public health problem that afflicts my patients.
总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Sethu Madhavan Madhavan其他文献
Sethu Madhavan Madhavan的其他文献
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{{ truncateString('Sethu Madhavan Madhavan', 18)}}的其他基金
Apolipoprotein L1 Interaction with SNARE Proteins in the Pathogenesis of Chronic Kidney Disease
载脂蛋白 L1 与 SNARE 蛋白在慢性肾脏病发病机制中的相互作用
- 批准号:
10400082 - 财政年份:2020
- 资助金额:
$ 16.09万 - 项目类别:
Apolipoprotein L1 Interaction with SNARE Proteins in the Pathogenesis of Chronic Kidney Disease
载脂蛋白 L1 与 SNARE 蛋白在慢性肾脏病发病机制中的相互作用
- 批准号:
10613925 - 财政年份:2020
- 资助金额:
$ 16.09万 - 项目类别:
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