Project 1: Molecular Impact of VWF on Clinical VWD

项目 1：VWF 对临床 VWD 的分子影响

• 批准号: 10113376
• 负责人: ROBERT R MONTGOMERY
• 金额: $ 33.35万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10113376
• 关键词: 1 year old; Acute; Adult; Affect; Age; Animal Model; Antibodies; Assessment tool; Binding; Biological Assay; Biology; Blood Platelets; Candidate Disease Gene; Carbohydrates; Cells; Child; Childbirth; Clinical; Clinical assessments; Code; Collagen; DNA; DNA Sequencing Facility; Databases; Defect; Diagnosis; Disease; Elderly; Engineered Gene; Enhancers; Enrollment; Epigenetic Process; F8 gene; Family member; Farming environment; Foundations; Frequencies; Funding; Genes; Genetic; Genomics; Genotype; Hemophilia A; Hemorrhage; Human; Individual; Introns; Label; Laboratories; Laboratory Study; Laser injury; Ligation; Modeling; Modification; Molecular; Mutation; Myosin ATPase; Newly Diagnosed; Operative Surgical Procedures; Pathway interactions; Patients; Phenotype; Physiological; Plasma; Platelet Membrane Glycoprotein IIb; Process; Program Research Project Grants; Proteins; Rattus; Research Design; Risk Factors; Rodent Model; Sampling; Severities; Stress; Symptoms; Tail; Testing; Thrombocytopenia; Thrombosis; Time; United States National Institutes of Health; VWF gene; Variant; Visit; age related; base; biobank; carbohydrate receptor; clinical phenotype; cohort; comparative genomic hybridization; follow-up; genome sequencing; head-to-head comparison; improved; in vivo; insight; mouse model; programs; promoter; prospective; receptor; recruit; reduce symptoms; thrombotic; treatment center; von Willebrand Factor; whole genome

Project 1 in the Zimmerman Program for the Biology of VWD (ZPB-VWD) is focused on the Molecular Impact of VWF on Clinical VWD. It consolidates the two existing cohorts – 1) retrospective PPG cohort previously diagnosed in the Zimmerman Program for the Molecular and Clinical Biology of VWD and 2) the prospective R01 cohort recruits. In Aim 1 laboratory studies are done longitudinally on the Type 1, 2, and 3 VWD subjects as well as the group with reduced VWF levels that we collectively call Low von Willebrand Factor that includes those that might have been previously labeled as “Mild VWD” with VWF <normal but little or no bleeding. These may be considered as having a risk factor for bleeding but not a disease. Not only will we study the changes with time of their laboratory phenotype but also study them with and interim Bleeding Assessment Score (iBAT) to semiquantitatively assess the amount of “new clinical bleeding” since BATs assess bleeding but the score saturates and cannot quantify interim bleeding. Additionally, Aim 1 will quantifiably evaluate potential abnormal binding to new matrix proteins (e.g. myosin) or new functional receptors (e.g. platelet GP IIb-IIIa (2b3a). In Aim 2 type 2 functional variants will be studied to determine the fidelity of diagnosis (types 2A, 2B, 2M, and 2N) between phenotypic assignments locally to those centrally assigned. Animal models of type 2 variants have been/will be developed and compared using bleeding and thrombosis testing (tail bleeding, template bleeding, VenaFlux, and Laser-injury assessment. Aim 3 will include subjects in our combined cohort who have type 1 or 3 VWD or LVWF and to these existing cohorts add existing, similarly defined, cohort from Kingston and Dublin but have no VWF mutation and are negative by Array Comparative Genome Hybridization (aCGH) or Multiplex Ligation-dependent Probe Amplification (MLPA). Within our cohort, we have at least 3 type 3 VWD subjects with no VWF sequence variant, are negative by aCGH, and have no anti-VWF antibodies. In addition we have >40 type 1 VWD and >180 LVWF subject samples with NSV and negative aCGH. Therefore we will first study these type 1 and 3 subjects by whole Genome Sequencing (WGS) using NGS sequencing in Core B. When individual candidate genes are identified, sequencing will be performed on the affected (AFM) and unaffected family members (UFM) to ascertain linkage with phenotype. Candidate SV will then be farmed out to Projects 1-4, based upon whether they are 1) VWF intronic changes (Project 1); 2) involve carbohydrates or carbohydrate receptors (Project 2); 3) mechanisms outside the VWF coding region (Project 3); or 4) suggest an epigenetic mechanism (Project 4). For frequent or scientifically unique causes that might be identified, animal models of these will be produced in Core C and studied in the various projects. Through Project 1 we expect to gain insight into the disease mechanisms causing VWD and how they affect laboratory and clinical phenotypes through developed animal models, and to assist with determining extragenic causes of both type 1 and type 3 VWD.

齐默尔曼VWD生物学计划（ZPB-VWD）的项目1侧重于分子影响