权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
DAVID P LILLICRAP
金额：
$ 26.05万
依托单位：
VERSITI WISCONSIN, INC.
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：
https://reporter.nih.gov/project-details/10584537
关键词：
Anabolism Area Attention Binding Binding Proteins Biology Blood Blood Coagulation Disorders Blood Platelets C-Type Lectins C2 Domain CRISPR/Cas technology Cells Chromatin Structure Code Collagen Consensus Deletion Mutation Development Disease Distant Elements Endocytosis Endothelial Cells Factor VIII Family Genes Genetic Genetic Enhancer Element Genetic Transcription Genetic Variation Genetic study Genome Genomic approach Genomics Genotype Hemorrhage Heterozygote Human Inherited Knock-out Knockout Mice Knowledge Ligand Binding Mediating Megakaryocytes Modification Mus Nuclear Nucleic Acid Regulatory Sequences Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Plasma Polysaccharides Population Prevalence Process Proteins RNA Splicing Regulation Role Signal Pathway Single Nucleotide Polymorphism Site Symptoms System Testing Transcriptional Activation Transgenic Mice Variant Vascular Endothelial Cell cell type cis acting element cohort disease phenotype experimental study genetic variant genome wide association study genomic locus humanized mouse in vitro Assay in vitro Model in vivo indexing member molecular pathology mouse model patient population programs promoter rare condition rare variant receptor receptor expression receptor mediated endocytosis study population syntaxin syntaxin-2 trafficking trait von Willebrand Disease von 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