Zimmerman Program on the Biology of VWD

项目总结：总体 关于von的分子和生物防治的剩余关键问题的计划项目资助 Von Willebrand病中的Willebrand因子。这个PPG由4个项目和3个核心组成，都是 专注于von Willebrand病及其导致功能障碍的机制，清除增加或增加 合成，以及碳水化合物修饰在VWF生物学中所起的作用。虽然这代表着一个新的PPG 应用程序，这个PPG利用了历史上先前存在的PPG的样本和生物数据 确诊的受试者，以及对预期招募的新的VWD受试者的R01拨款。项目1包括旨在 确定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抗体在 3型VWD，以及VWD和VWD变异体动物模型的建立。低von的受试者 威勒布兰德因子(LVWF)和没有序列变异的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 基于候选路径的项目1、2、3或4所研究的机制。项目2将定义 VWF的碳水化合物修饰通过N-和O-糖链的测定，研究其糖链 血浆、血管内皮细胞和血小板VWF的差异以及使用MS-GOGCOMIC和 糖蛋白组学方法。将在老鼠身上建立模型系统，以反映在人类身上发现的变化 机械装置。项目3将研究上游监管控制作为一种导致VWD的机制。单元格 将使用从VWD患者获得的BOEC来研究VWF的生物学，并用于检查VWF的作用 促进剂和增强剂。基因工程小鼠将研究清除的机制 受体改变了VWF的浓度。项目4将研究VWF的转录调控及其抑制作用 与microRNA的结合。该项目还将研究表观遗传学在调节血浆VWF和 慢性炎症对上述机制的影响。有三个核心来支持此PPG。核心A是 管理核心，将促进信息、数据、患者样本和生物数据的交换。会的 还将监督10个初级临床中心，这些中心将跟踪我们登记的受试者。核心B将会做 VWF非常低或不存在且VWF测序正常的受试者的全基因组测序。 Core C将为每个项目开发动物模型，以进一步研究VWD的机制。 这些研究将综合研究导致VWF减少或异常的独特机制 在VWD。

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.