Molecular and Clinical Biology of VWD

VWD 的分子和临床生物学

• 批准号: 7458716
• 负责人: ROBERT R MONTGOMERY
• 金额: $ 195.69万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458716
• 关键词: Molecular; Clinical; Biology; VWD

DESCRIPTION (provided by applicant): This Program Project on VWD in the US is directed at the molecular and clinical understanding of this disorder. There is a lack in understanding the genetic causes of "low or abnormal VWF" and the molecular mechanisms involved in the pathophysiology and biology. While a large number of individuals have low or abnormal VWF with abnormal bleeding symptoms, it is not scientifically clear if this is a "disease" or that VWF is a continuous risk-factor for bleeding. The general understanding by practicing physicians about this group of disorders is not optimal and how these patients should be evaluated and treated has been often unclear.. This PPG will primarily focus on type 1 VWD, but will include some type 2 VWD patients correlate clinical and laboratory abnormalities. We will determine if bleeding and low VWF are genetically linked to the VWF gene locus; and if not, what is the magnitude of other modifying genes on either the clinical or the laboratory phenotype. Project 1 will determine the clinical and laboratory phenotype of a large cohort of VWD patients with particular emphasis on type 1 and carriers of type 3 VWD. Selected type 2 variants will be studied to contrast their phenotypic penetrance, clinical penetrance, and as a relative validation of the bleeding score. Full laboratory phenotyping and full-length DNA VWF gene sequencing will be undertaken to characterize these patients and the impact of allelic inheritance within their family on bleeding and laboratory phenotype. The laboratory features, bleeding symptoms and scoring of a subgroup containing women who exhibit menorrhagia as a major symptom will be studied for bleeding score and laboratory VWF phenotyping Project 2 will define the mechanisms behind the clinical and laboratory phenotypes/genotypes identified in Project 1, 3, and 4. Project 3 will identify modifying genes that affect the level, survival, function, and clinical manifestations of abnormal VWF. This project will utilize large, well characterized families with VWD (identified in Project 1/Core A) to identify associations with areas of the human genome other than the VWF locus on Chromosome 12. Project 4 will explore abnormalities in an extended promoter region, splice-junction mutations, and specific VWF-haplotypes as causes of abnormal or low VWF. It will make use of samples collected through Core A in which coding region mutations of the VWF gene are not identified. This project will also further study non-linked VWD for other causes outside the VWF locus. These 4 projects will be supported by Core A for administrative support and patient acquisition and Core B Clinical Laboratory and Sequencing Core.

描述（由申请人提供）： 美国VWD的该计划项目针对该疾病的分子和临床理解。缺乏了解“低或异常VWF”的遗传原因以及病理生理学和生物学中涉及的分子机制。尽管大量个体患有异常出血症状的VWF较低或异常，但科学上尚不清楚这是“疾病”，还是VWF是出血的连续风险因素。实践医生对这组疾病的一般理解并不是最佳的，以及如何评估和治疗这些患者通常不清楚。该PPG主要集中在1型VWD上，但将包括某些2型VWD患者相关的临床和实验室异常。我们将确定出血和低VWF是否与VWF基因基因座相连。如果没有，其他修饰基因在临床或实验室表型上的幅度是多少。项目1将确定大量VWD患者队列的临床和实验室表型，并特别强调3型VWD的1型和载体。将研究选定的2型变体，以对比其表型渗透率，临床渗透率以及出血评分的相对验证。将进行完整的实验室表型和全长DNA VWF基因测序，以表征这些患者以及家族中等位基因遗传对出血和实验室表型的影响。将研究表现出月经症状作为主要症状的女性的实验室特征，出血症状和评分，以进行出血得分和实验室VWF表型项目2的出血，将定义临床和实验室表型/基因型背后的机制。异常VWF。 This project will utilize large, well characterized families with VWD (identified in Project 1/Core A) to identify associations with areas of the human genome other than the VWF locus on Chromosome 12. Project 4 will explore abnormalities in an extended promoter region, splice-junction mutations, and specific VWF-haplotypes as causes of abnormal or low VWF.它将利用通过核心A收集的样品，在该样品中，未鉴定VWF基因的编码区域突变。该项目还将进一步研究VWF基因座以外的其他原因的非链接VWD。这4个项目将得到核心A的支持，以提供行政支持和患者的获取以及核心B临床实验室和测序核心。