Project-004

项目-004

• 批准号: 10584541
• 负责人: ROBERT R MONTGOMERY
• 金额: $ 38万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584541
• 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

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.

项目摘要：总体 该计划项目授予涉及有关von的分子和生物控制的关键问题 von Willebrand疾病中的Willebrand因素。该PPG由4个项目和3个核心组成 专注于冯·威勒氏疾病和机制，导致其功能障碍，清除率增加或增加 合成，碳水化合物修饰在VWF生物学中的作用。虽然这代表了一个新的PPG 应用，此PPG利用了先前存在的PPG的样品和生物数据 诊断出对新的VWD受试者的R01赠款，并获得了前瞻性招募的新型VWD受试者。项目1包括 定义VWF浓度的纵向变化以及半定量出血评估的变化 在随访间隔中，2型VWD诊断的保真度，抗VWF抗体的频率 3型VWD，以及VWD和VWD变体动物模型的开发。 von低的受试者 将在完整的核心B中研究Willebrand因子（LVWF）和没有序列变体的1或3型VWD 基因组测序。确定的异常情况将在其家庭成员中通过项目1和 基于候选途径的项目1、2、3或4研究的机制。项目2将定义 通过确定N-和O-Glycan剖面对VWF的碳水化合物修饰，研究聚糖 血浆，内皮和血小板VWF的差异以及使用MS-Glycomic和 糖蛋白质组学方法。模型系统将在鼠标中设立，以反映人类中发现的变化 机制。项目3将研究上游监管控制作为导致VWD的机制。细胞 将使用从VWD患者获得的BOEC研究VWF的生物学，并用于检查 发起人和增强剂。基因工程的小鼠将研究间隙的机制 受体改变了VWF浓度。项目4将研究VWF的转录调节和抑制作用 与microRNA。该项目还将研究表观遗传学在调节等离子体VWF和 慢性炎症对这些机制的影响。有三个核心可以支持此PPG。核心A是 行政核心将有助于交换信息，数据和患者样本和生物数据。会 还监督将遵循我们入学受试者的10个主要临床中心。核心B会做 对具有正常VWF测序的非常低或缺乏VWF的受试者的整个基因组测序。 核心C将为每个项目开发动物模型，以进一步研究VWD机制。 这些研究将共同​​研究导致VWF降低或异常的独特机制 在VWD中。