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Zimmerman Program on the Biology of VWD

齐默尔曼 VWD 生物学计划

基本信息

批准号：
10584527
负责人：
ROBERT R MONTGOMERY
金额：
$ 262.95万
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/10584527
关键词：
Address Affect Aging Animal Model Animals Antibodies Binding Binding Proteins Biological Biological Assay Biological Models Biology Blood Platelets Carbohydrates Cellular biology Chronic Clinical Code Data Development Diagnosis Diagnostic Endothelial Cells Endothelium Engineering Enhancers Enrollment Epigenetic Process Family Family member Foundations Frequencies Functional disorder Gene Mutation Genes Genetic Genetic Transcription Genetic Variation Genetically Engineered Mouse Glycobiology Grant Hemorrhage Histone Acetylation Human Individual Inflammation Introns Lectin Methods Methylation MicroRNAs Modification Molecular Mus Mutation Pathology Pathway interactions Patients Plasma Play Polysaccharides Program Research Project Grants Regulatory Pathway Role Sampling Structure Symptoms TCF7L2 gene Time Transcriptional Regulation United States Upstream Enhancer VWF gene Variant animal model development carbohydrate structure clinical center clinical diagnosis cohort comparative genomic hybridization follow-up genetic linkage genome sequencing glycoproteomics indexing participant enrollment programs promoter prospective racial difference receptor recruit single-cell RNA sequencing syntaxin von Willebrand Disease von Willebrand Factor whole genome

项目摘要

PROJECT SUMMARY: OVERALL This Program Project Grant on remaining critical issues concerning the molecular and biologic control of von Willebrand factor in von Willebrand disease. This PPG is comprised of 4 projects and 3 cores that are all focused on von Willebrand disease and mechanisms causing its dysfunction, increased clearance or increased synthesis, and the role carbohydrate modification play in VWF biology. While this represents a new PPG application, this PPG makes use of the samples and biodata from the pre-existing PPG on historically diagnosed subjects and an R01 grant on new VWD subjects recruited prospectively. Project 1 includes aims to define longitudinal changes in VWF concentration and changes in semiquantitative bleeding assessment during follow-up intervals, the fidelity of the diagnosis of type 2 VWD, the frequency of antibodies to VWF in type 3 VWD, and the development of animal models of VWD and VWD variants. Subjects with low von Willebrand factor (LVWF), and type 1 or 3 VWD with no sequence variants will be studied in Core B with full genome sequencing. Abnormalities identified will be sought in their family members through Project 1 and the mechanism studied by projects 1, 2, 3, or 4 based on candidate pathway. Project 2 will define the role of carbohydrate modification of VWF through determination of N- and O-glycan profiles, study the glycan differences in plasma, endothelial and platelet VWF, and racial differences using MS-glycomic and glycoproteomic approaches. Model systems will be set up in mice to mirror the changes found in human mechanisms. Project 3 will examine the upstream regulatory control as a mechanism causing VWD. The cell biology of VWF will be studied using BOECs obtained from patients with VWD and used to examine the role of promoters and enhancers. Genetically engineered mice will study the mechanisms by which clearance receptors alter VWF concentration. Project 4 will study the transcription regulation of VWF and the inhibition with microRNAs. This project will also examine the role of epigenetics in modulating plasma VWF and the effect of chronic inflammation on these mechanisms. There are three cores to support this PPG. Core A is the administrative core that will facilitate exchange of information, data, and patient samples and biodata. It will also oversee the 10 Primary Clinical Centers that will be following our enrolled subjects. Core B will be doing whole genome sequencing of subjects with very low or absent VWF that have had normal VWF sequencing. Core C will develop animal models for each of the projects to further their studies on VWD mechanisms. Together these studies will comprehensively study unique mechanisms that lead to reduced or abnormal VWF in VWD.

项目总结：总体

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Desmopressin responsiveness by age in type 1 von Willebrand disease.

1 型冯维勒布兰德病中不同年龄的去氨加压素反应。

DOI：
10.1002/rth2.12354
发表时间：
2020
期刊：
Research and practice in thrombosis and haemostasis
影响因子：
4.6
作者：
Goldberg,Nicola;Nisenbaum,Rosane;Song,Hong;Lillicrap,David;Teitel,Jerome;James,Paula;Sholzberg,Michelle
通讯作者：
Sholzberg,Michelle

Investigating the clearance of VWF A-domains using site-directed PEGylation and novel N-linked glycosylation.

DOI：
10.1111/jth.14785
发表时间：
2020-06
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
0
作者：
Fazavana J;Brophy TM;Chion A;Cooke N;Terraube V;Cohen J;Parng C;Pittman D;Cunningham O;Lambert M;O'Donnell JS;O'Sullivan JM
通讯作者：
O'Sullivan JM

New developments in von Willebrand disease.

DOI：
10.1111/bjh.16681
发表时间：
2020-11
期刊：
British journal of haematology
影响因子：
6.5
作者：
Fogarty H;Doherty D;O'Donnell JS
通讯作者：
O'Donnell JS

von Willebrand Factor Antigen, von Willebrand Factor Propeptide, and ADAMTS13 in Carotid Stenosis and Their Relationship with Cerebral Microemboli.

DOI：
10.1055/s-0040-1715440
发表时间：
2021-01
期刊：
Thrombosis and haemostasis
影响因子：
6.7
作者：
Murphy SJX;Lim ST;Hickey F;Kinsella JA;Smith DR;Tierney S;Egan B;Feeley TM;Murphy SM;Collins DR;Coughlan T;O'Neill D;Harbison JA;Madhavan P;O'Neill SM;Colgan MP;O'Donnell JS;O'Sullivan JM;Hamilton G;McCabe DJH
通讯作者：
McCabe DJH

Pregnancy and delivery in women with von Willebrand disease.