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Zimmerman Program on the Biology of VWD

Zimmerman Program on the Biology of VWD
齐默尔曼 VWD 生物学计划
批准号:
10379431
负责人:
ROBERT R MONTGOMERY
金额:
$263.04万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-03-15 至 2024-02-29

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中文摘要
翻译
项目概要:总体 该计划项目赠款对剩余的关键问题有关的分子和生物控制冯 血管性血友病中的血友病因子该PPG由4个项目和3个核心组成, 主要关注血管性血友病及其引起功能障碍、清除率增加或 合成,以及碳水化合物修饰在VWF生物学中的作用。虽然这代表了一个新的PPG 在应用中,本PPG使用了历史上已有PPG的样本和生物数据。 诊断的受试者和R 01补助金的新VWD受试者前瞻性招募。项目1的目的是 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诊断的准确性,VWF抗体的频率, 3型VWD,以及VWD和VWD变体的动物模型的开发。低von受试者 将在核心B中研究Willebrand因子(LVWF)和无序列变异的1型或3型VWD, 基因组测序将通过项目1和 根据候选途径,项目1、2、3或4研究的机制。项目2将确定 通过测定N-和O-聚糖谱对VWF进行碳水化合物修饰, 血浆、内皮和血小板VWF的差异,以及使用MS-糖基化和 糖蛋白质组学方法。将在小鼠中建立模型系统,以反映在人类中发现的变化 机制等项目3将研究上游监管控制作为引起VWD的机制。细胞 将使用从VWD患者获得的BOEC研究VWF的生物学, 启动子和增强子。基因工程小鼠将研究清除的机制, 受体改变VWF浓度。项目四研究VWF的转录调控及抑制VWF的作用 microRNA。该项目还将研究表观遗传学在调节血浆VWF和VWF中的作用。 慢性炎症对这些机制的影响。有三个核心来支持这个PPG。核心A是 行政核心,将促进信息,数据和患者样本和生物数据的交流。它将 我们还将监督10个主要临床中心,这些中心将跟踪我们招募的受试者。核心B将做 具有非常低或缺乏VWF的受试者的全基因组测序,所述受试者具有正常VWF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。 这些研究将全面研究导致VWF减少或异常的独特机制 在VWD。
英文摘要
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.
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Project 1: Molecular Impact of VWF on Clinical VWD
  • 批准号:
    10113376
  • 项目类别:
  • 资助金额:
    $33.35万
  • 财政年份:
    2019
  • 负责人:
    ROBERT R MONTGOMERY
  • 依托单位:
Project-004
  • 批准号:
    10584541
  • 项目类别:
  • 资助金额:
    $38.0万
  • 财政年份:
    2019
  • 负责人:
    ROBERT R MONTGOMERY
  • 依托单位:
Project-004
  • 批准号:
    10379439
  • 项目类别:
  • 资助金额:
    $34.21万
  • 财政年份:
    2019
  • 负责人:
    ROBERT R MONTGOMERY
  • 依托单位:
Project 1: Molecular Impact of VWF on Clinical VWD
  • 批准号:
    10379435
  • 项目类别:
  • 资助金额:
    $29.93万
  • 财政年份:
    2019
  • 负责人:
    ROBERT R MONTGOMERY
  • 依托单位:
海外基金