Zimmerman Program for the Molecular and Clinical Biology of VWD

齐默尔曼 VWD 分子和临床生物学项目

• 批准号: 8424981
• 负责人: ROBERT R MONTGOMERY
• 金额: $ 188.64万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424981
• 关键词: Address; African American; Biology; Canada; Clinical; Code; Cohort Studies; Collaborations; Country; Diagnosis; Diagnostic; Disease; Dominant-Negative Mutation; European Union; Foundations; Functional disorder; Funding; Future; General Population; Genetic Polymorphism; Guidelines; Hemophilia A; Hemorrhage; In Vitro; Individual; International; Laboratories; Menorrhagia; Molecular; Molecular Biology; Mus; Mutation; Names; National Heart, Lung, and Blood Institute; Other Genetics; Participant; Pathologic; Pathway interactions; Patients; Phenotype; Pilot Projects; Plasma; Prevalence; Program Research Project Grants; Public Health; Quality of life; Recording of previous events; Research; Research Personnel; Staging; Symptoms; Testing; Time; United Kingdom; United States; United States National Institutes of Health; VWF gene; Variant; abstracting; base; clinical phenotype; cohort; diagnosis evaluation; disease diagnosis; genome wide association study; improved; in vivo; interest; multidisciplinary; next generation sequencing; programs; treatment center; von Willebrand Disease; von Willebrand Factor

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.

描述（由申请人提供）：这是一份标题为VWD分子和临床生物学齐默尔曼项目的计划项目资助HL 081588的6-10年完整更新申请。该项目开始作为表征在美国诊断为VWD的患者的一种手段，并将其与我国以及加拿大和欧盟研究的队列中的分子、实验室表型和临床表型相关联。该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的问题，这些测试在非洲裔美国人中新定义的常见多态性方面表现不佳。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。 一些较新的试点研究也将研究VWD对临床月经过多的影响和VWD患者的生活质量研究。项目2（Haberichter）研究VWF突变的体内和体外相关性。 在小鼠中，将定义清除机制，以及个体（加速清除是1C型VWD的原因）是否通过正常途径增加清除或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。在该PPG以及加拿大和欧盟队列中，已确定受试者的VWF水平相当低，但未发现VWF编码区突变。这些研究的数量不足以系统地研究这一现象，但总体而言，这一群体有望成为可能。行政核心不仅监督该计划的日常管理，还维护一级和二级临床中心的支持性临床网络。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，并将协调下一代全VWF基因测序（项目1和3）和GWAS相关测序。总之，PPG将为VWD的适当诊断和表型理解奠定基础-无论是在美国还是在世界各地。