Project-004

项目-004

• 批准号: 10379439
• 负责人: ROBERT R MONTGOMERY
• 金额: $ 34.21万
• 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/10379439
• 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; Lead; 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; base; carbohydrate structure; clinical center; clinical diagnosis; cohort; comparative genomic hybridization; follow-up; genetic linkage; genome sequencing; glycoproteomics; indexing; 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.

项目概要：总体 该计划项目资助有关冯的分子和生物控制的剩余关键问题 血管性血友病的维勒布兰德因素。这个PPG由4个项目和3个核心组成，全部是 专注于冯维勒布兰德病和导致其功能障碍、清除增加或增加的机制 合成，以及碳水化合物修饰在 VWF 生物学中的作用。虽然这代表着新的 PPG 应用程序中，该 PPG 使用历史上先前存在的 PPG 中的样本和生物数据 诊断受试者和前瞻性招募的新 VWD 受试者的 R01 补助金。项目 1 的目标包括 定义 VWF 浓度的纵向变化和半定量出血评估的变化 在随访期间，2 型 VWD 诊断的保真度、VWF 抗体的频率 3 型 VWD，以及 VWD 和 VWD 变体动物模型的开发。低 von 的受试者 血友病因子 (LVWF) 和无序列变异的 1 型或 3 型 VWD 将在核心 B 中进行全面研究 基因组测序。将通过项目 1 和项目 1 寻找其家庭成员中发现的异常情况。 项目 1、2、3 或 4 基于候选路径研究的机制。项目 2 将定义以下角色： 通过测定 N- 和 O- 聚糖谱对 VWF 进行碳水化合物修饰，研究聚糖 血浆、内皮和血小板 VWF 的差异，以及使用 MS-糖组学和种族差异 糖蛋白质组学方法。将在小鼠体内建立模型系统，以反映在人类中发现的变化 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 来研究 VWF 的生物学，并用于检查 启动子和增强子。基因工程小鼠将研究清除机制 受体改变 VWF 浓度。项目4将研究VWF的转录调控及其抑制作用 与微小RNA。该项目还将研究表观遗传学在调节血浆 VWF 和 慢性炎症对这些机制的影响。共有三个核心支持此 PPG。核心A是 管理核心将促进信息、数据以及患者样本和生物数据的交换。它将 还监督将跟踪我们登记受试者的 10 个主要临床中心。核心B会做 对具有极低或缺乏 VWF 且 VWF 测序正常的受试者进行全基因组测序。 Core 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​​全面研究导致 VWF 减少或异常的独特机制 在 VWD 中。