Zimmerman Program for the Molecular and Clinical Biology of VWD

描述(由申请人提供)：这是一个完整的续签申请，为期6-10年的项目拨款HL081588的齐默尔曼计划的VWD的分子和临床生物学。这个项目最初是为了确定美国被诊断为VWD的患者的特征，并将他们在分子、实验室表型和我国临床表型以及在加拿大和欧盟研究的队列中联系起来。这项PPG发现了历史VWD诊断的保真度问题，以及使用某些测试表现不佳的问题，这些测试与新定义的非裔美国人常见的多态有关。项目1(蒙哥马利)提出了提高VWD诊断准确性的研究，并研究了更好地对比VWD诊断的临床、临床实验室和研究相关性的方法。一些较新的初步研究也将研究VWD对VWD患者临床月经过多和生活质量的影响。项目2(Haberichter)研究了VWF突变的体内和体外相关性。在小鼠中，清除机制将被定义，以及个体，由于加速清除是1C型VWD的原因，是通过正常途径增加清除，还是通过病理途径增加清除。项目3(Lillicrap/Goodeve探索了降低血浆和/或细胞VWF的更广泛机制。在这个PPG内以及在加拿大和欧盟的队列中，已经发现受试者的VWF非常低，但在这些受试者中没有发现VWF的编码区突变。就个人而言，这些研究的数量不足以系统地研究这一现象，但总体来说，这一群体有望实现这一目标。行政核心不仅监督这个项目的日常管理，还维护一个由初级和二级临床中心组成的支持临床网络。临床实验室核心执行临床实验室测试(所有三个项目都需要)，即VWF的编码序列，并将协调下一代VWF全基因测序(项目1和3)和与GWAS相关的测序。总而言之，PPG将为在美国和全世界对VWD进行适当的诊断和表型理解奠定基础。

DESCRIPTION (provided by applicant): This is a completive renewal application for years 6-10 of Program Project Grant HL081588 entitled the Zimmerman Program for the Molecular and Clinical Biology of VWD. This project began as a means of characterizing patients diagnosed with VWD in the USA and correlating them at a molecular, laboratory phenotype, and clinical phenotype within our country as well as with cohorts studied in Canada and the European Union. This PPG has identified problems with the fidelity of the historical VWD diagnosis and problems with using certain tests that perform poorly with newly define common polymorphisms in African American. Project 1 (Montgomery) proposes studies to improve the fidelity of the diagnosis of VWD and studies approaches to better contrast the clinical, clinical lab, and research correlation of the VWD diagnosis. Some newer pilot studies will also study the impact of VWD on clinical menorrhagia and Quality of Life studies in VWD patients. Project 2 (Haberichter) studies the in vivo and in vitro correlates of VWF mutations. In the mouse, clearance mechanisms will be defined and whether an individual, with accelerated clearance as the reason for type 1C VWD, has increased clearance through normal pathways or increased clearance through pathologic pathways. Project 3 (Lillicrap/Goodeve explores broader mechanisms for reduced plasma, and/or cellular, VWF. Within this PPG and in both the Canadian and European Union Cohorts, subjects have been identified with quite low VWF but in whom no coding region mutation of VWF are identified. Individually, these studies have insufficient numbers to systematically study this phenomenon, but collectively this group is expected to be enabling. The Administrative Core not only oversees the day-to-day management of this Program but also maintains a supporting clinical network of Primary and Secondary Clinical Centers. The Clinical Laboratory Core performs the clinical laboratory testing (needed by all three projects), the coding sequence of VWF, and will coordinate the next-generation sequencing the full VWF gene (Project 1 and 3) and GWAS-associated sequencing. Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world.