Zimmerman Program for the Molecular and Clinical Biology of VWD

描述（由申请人提供）：这是一份完整的VWD齐默尔曼分子和临床生物学项目资助HL081588项目6-10年的续期申请。该项目最初是作为一种表征美国被诊断为VWD的患者的手段，并在我国以及在加拿大和欧盟研究的队列中通过分子、实验室表型和临床表型将他们联系起来。本PPG已经确定了历史VWD诊断的保真度问题，以及使用某些测试在非洲裔美国人中新定义的常见多态性表现不佳的问题。Project 1 （Montgomery）提出了提高VWD诊断保真度的研究，以及更好地对比VWD诊断的临床、临床实验室和研究相关性的研究方法。一些较新的试点研究也将研究VWD对临床月经过多和VWD患者生活质量的影响。项目2 （Haberichter）研究了VWF突变的体内和体外相关因素。在小鼠中，清除机制将被定义，以及以清除加速为1C型VWD原因的个体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）探索降低血浆和/或细胞VWF的更广泛机制。在该PPG以及加拿大和欧盟的队列中，已发现受试者的VWF相当低，但未发现VWF编码区突变。单独来看，这些研究的数量不足以系统地研究这一现象，但总的来说，这一组研究有望发挥作用。行政核心不仅监督该计划的日常管理，而且还维持初级和二级临床中心的支持临床网络。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），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gwas相关测序。总之，该PPG将为美国和全世界的VWD的适当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.