Project 2: Molecular Impact of Carbohydrates on VWF Biology
项目 2:碳水化合物对 VWF 生物学的分子影响
基本信息
- 批准号:10379436
- 负责人:
- 金额:$ 46.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-15 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AgeAnabolismAnimalsBindingBiologicalBiologyBloodBlood PlateletsCRISPR/Cas technologyCarbohydratesChromosome 12ClinicalCohort StudiesComplexDataDefectDiseaseEndothelial CellsEnrollmentEtiologyGene MutationGenesGlycoside HydrolasesHumanIn VitroInvestigationIrelandLectinLectin ReceptorsLinkLoveMass Spectrum AnalysisMediatingMethodologyModificationMolecularMusNaturePathogenesisPatientsPhenotypePlasmaPlayPolysaccharidesProteolysisResourcesRoleSeriesSiteSmall Interfering RNAStructureTimeanimal datacarbohydrate structurecell typecohortexomeexperimental studygenomic locusglycoproteomicsglycosylationglycosyltransferasehuman datain vivoindividual patientinsightinterestknock-downnovelnovel strategiespatient subsetsprofiles in patientsprogramsreceptorsextraffickingvon Willebrand Diseasevon Willebrand Factor
项目摘要
PROJECT SUMMARY: PROJECT 2
Type 1 VWD is characterized by a partial quantitative deficiency of VWF. Although it accounts for 70% of
all cases of VWD, the molecular mechanisms underlying the pathogenesis of type 1 VWD remain poorly
understood. However, linkage studies have shown that reduced plasma VWF levels (particularly in patients
with mild to moderate reductions in the range 30 - 50 IU/dL) are independent of the VWF gene on
chromosome 12. Accumulating data from both animal and human studies have demonstrated that the
complex glycan determinants expressed on VWF play critical roles in regulating many aspects of its
biology, including synthesis, proteolysis and clearance. Aim 1 of this project will investigate how VWF N-
and O-glycan structures vary in a large cohort of patients with comprehensively phenotyped VWD already
enrolled through 1) the Zimmerman program, (2) the Canadian type 1 VWD study and (3) the Low VWF
Ireland Cohort study. Given the complex heterogeneous nature of the N- and O- carbohydrate structures
expressed on human VWF, this unique combined clinical resource will for the first time provide adequate
power to enable elucidation of the role of VWF glycans in VWD pathogenesis. In Aim 2, a subset of patients
with type 1 VWD and Low VWF in whom glycan abnormalities have been identified will be selected for
further analysis. In this cohort, the N- and O-glycan structures of VWF will be definitively sequenced using
state-of-the-art mass spectroscopy glycoproteomic analysis. Finally, using a number of novel parallel
strategies, Aim 3 of the project will focus on (1) investigating the mechanisms underlying abnormal VWF
glycosylation in patients with type 1 VWD and Low VWF, and (2) determining whether VWF carbohydrate
modifications play a direct causal role in mediating VWD pathogenesis (e.g. by reducing biosynthesis or
modulating enhanced clearance).
项目总结:项目2
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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James O'Donnell其他文献
James O'Donnell的其他文献
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{{ truncateString('James O'Donnell', 18)}}的其他基金
Project 2: Molecular Impact of Carbohydrates on VWF Biology
项目 2:碳水化合物对 VWF 生物学的分子影响
- 批准号:
10113377 - 财政年份:2019
- 资助金额:
$ 46.94万 - 项目类别:
Project 2: Molecular Impact of Carbohydrates on VWF Biology
项目 2:碳水化合物对 VWF 生物学的分子影响
- 批准号:
10584535 - 财政年份:2019
- 资助金额:
$ 46.94万 - 项目类别:
Project 2: Molecular Impact of Carbohydrates on VWF Biology
项目 2:碳水化合物对 VWF 生物学的分子影响
- 批准号:
9891091 - 财政年份:
- 资助金额:
$ 46.94万 - 项目类别:
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