Project 3: Contribution of Non-VWF Genomic Variants to Quantitative Von Willebrand Factor Pathologies
项目 3:非 VWF 基因组变异对定量冯维勒布兰德因子病理学的贡献
基本信息
- 批准号:10584537
- 负责人:
- 金额:$ 26.05万
- 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 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AnabolismAreaAttentionBindingBinding ProteinsBiologyBloodBlood Coagulation DisordersBlood PlateletsC-Type LectinsC2 DomainCRISPR/Cas technologyCellsChromatin StructureCodeCollagenConsensusDeletion MutationDevelopmentDiseaseDistantElementsEndocytosisEndothelial CellsFactor VIIIFamilyGenesGeneticGenetic Enhancer ElementGenetic TranscriptionGenetic VariationGenetic studyGenomeGenomic approachGenomicsGenotypeHemorrhageHeterozygoteHumanInheritedKnock-outKnockout MiceKnowledgeLigand BindingMediatingMegakaryocytesModificationMusNuclearNucleic Acid Regulatory SequencesPathogenicityPathologicPathologyPathway interactionsPatientsPhenotypePlasmaPolysaccharidesPopulationPrevalenceProcessProteinsRNA SplicingRegulationRoleSignal PathwaySingle Nucleotide PolymorphismSiteSymptomsSystemTestingTranscriptional ActivationTransgenic MiceVariantVascular Endothelial Cellcell typecis acting elementcohortdisease phenotypeexperimental studygenetic variantgenome wide association studygenomic locushumanized mousein vitro Assayin vitro Modelin vivoindexingmembermolecular pathologymouse modelpatient populationprogramspromoterrare conditionrare variantreceptorreceptor expressionreceptor mediated endocytosisstudy populationsyntaxinsyntaxin-2traffickingtraitvon Willebrand Diseasevon Willebrand Factor
项目摘要
PROJECT SUMMARY: PROJECT 3
The pathogenic basis of the inherited bleeding disorder, von Willebrand disease (VWD), represents a spectrum
of genetic mechanisms and variants. While the qualitative type 2 forms of VWD are the result of missense
substitutions in domains of von Willebrand factor (VWF) involved in ligand binding, the quantitative traits, type
1 and 3 VWD, are associated with many different sequence variants throughout the VWF gene. However,
following detailed genotyping of the VWF coding region and splices sites in >500 type 1 and >100 type 3 VWD
cases, pathogenic variants have not been identified in ~35% and ~15% of patients, respectively. This
evidence, along with repeated results from large genome wide association studies (GWAS), strongly supports
the involvement of genes in addition to VWF in the regulation of plasma VWF levels. The overall aim of this
project is to explore the role of sequence variants at genetic loci other than the VWF gene as contributors to
low VWF pathological states. Three specific aims will be pursued in this project. In each of these aims, we will
use genomic information derived from sequencing of a large patient population with type 1, type 3 and “Low
VWF” levels in whom prior analysis has failed to identify pathogenic sequence variants. In Aim #1, genetic
variability in the 5' upstream region of the VWF locus will be examined to determine the influence on VWF
transcriptional activation. Two areas of the VWF regulatory region will be examined: the proximal promoter,
where cis-acting elements interacting with the Hippo signaling pathway will be examined, and a distant super-
enhancer element ~45 kb upstream of VWF. In Aim #2, we will evaluate the role of sequence variants of three
genes involved in VWF synthesis, storage and secretion. Variants of STX-2, STXBP5 and TC2N will be
examined in endothelial cell-based in vitro models and in vivo, in KO mouse models for these genes. Lastly,
we will investigate several VWF clearance receptors (CLEC4M, Stablin-2 and SCARA5) and regulators of the
endocytic process (FCHO2 and RAB5C), all of which have been implicated in the regulation of plasma VWF
levels in GWAS studies. These experiments will incorporate the development of new transgenic mouse models
to assess clearance phenotypes, and will explore the regions and modifications to VWF that mediate the
interaction with its clearance receptors.
项目总结:项目3
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('DAVID P LILLICRAP', 18)}}的其他基金
Project 3: Contribution of Non-VWF Genomic Variants to Quantitative Von Willebrand Factor Pathologies
项目 3:非 VWF 基因组变异对定量冯维勒布兰德因子病理学的贡献
- 批准号:
10113378 - 财政年份:2019
- 资助金额:
$ 26.05万 - 项目类别:
Project 3: Contribution of Non-VWF Genomic Variants to Quantitative Von Willebrand Factor Pathologies
项目 3:非 VWF 基因组变异对定量冯维勒布兰德因子病理学的贡献
- 批准号:
10379437 - 财政年份:2019
- 资助金额:
$ 26.05万 - 项目类别:
Influence of the Host Microbiome on the Mechanism of FVIII Immunogenicity: Project 3
宿主微生物组对 FVIII 免疫原性机制的影响:项目 3
- 批准号:
10406335 - 财政年份:2018
- 资助金额:
$ 26.05万 - 项目类别:
Influence of the Host Microbiome on the Mechanism of FVIII Immunogenicity: Project 3
宿主微生物组对 FVIII 免疫原性机制的影响:项目 3
- 批准号:
10162327 - 财政年份:2018
- 资助金额:
$ 26.05万 - 项目类别:
Core A-ADMINISTRATIVE AND CLINICAL ACQUISITION CORE
核心 A-管理和临床获取核心
- 批准号:
7114036 - 财政年份:2005
- 资助金额:
$ 26.05万 - 项目类别:
Core A-ADMINISTRATIVE AND CLINICAL ACQUISITION CORE
核心 A-管理和临床获取核心
- 批准号:
7524665 - 财政年份:
- 资助金额:
$ 26.05万 - 项目类别:
Core A-ADMINISTRATIVE AND CLINICAL ACQUISITION CORE
核心 A-管理和临床获取核心
- 批准号:
7524670 - 财政年份:
- 资助金额:
$ 26.05万 - 项目类别:
Core A-ADMINISTRATIVE AND CLINICAL ACQUISITION CORE
核心 A-管理和临床获取核心
- 批准号:
7652348 - 财政年份:
- 资助金额:
$ 26.05万 - 项目类别:
Project 3: Contribution of Non-VWF Genomic Variants to Quantitative Von Willebrand Factor Pathologies
项目 3:非 VWF 基因组变异对定量冯维勒布兰德因子病理学的贡献
- 批准号:
9891092 - 财政年份:
- 资助金额:
$ 26.05万 - 项目类别:
Core A-ADMINISTRATIVE AND CLINICAL ACQUISITION CORE
核心 A-管理和临床获取核心
- 批准号:
7885358 - 财政年份:
- 资助金额:
$ 26.05万 - 项目类别:
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