MOLECULAR IMPACT OF VWF ON CLINICAL VWD

VWF 对临床 VWD 的分子影响

• 批准号: 7885354
• 负责人: ROBERT R MONTGOMERY
• 金额: $ 36.48万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2012-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885354
• 关键词: Address; Adhesions; Adult; Affect; African American; Age; Alleles; Antibodies; Attention; Binding; Biological Assay; Biology; Blood Platelets; Blood Vessels; Blood typing procedure; Candidate Disease Gene; Clinic; Clinical; Clinical Research; Clinical assessments; Coagulation Process; Code; Collagen; Complex; Control Groups; DDAVP; DNA; Defect; Diagnosis; Diagnostic; Disease; Etiology; European Union; Event; Family; Family Study; Family member; Foundations; Frequencies; Gene Abnormality; Gene Expression; Gene Mutation; Gene-Modified; Genes; Genetic; Glycoproteins; Goals; Grant; Gynecology; Hemophilia A; Hemorrhage; Hemostatic Agents; Hemostatic function; Hour; Hypothyroidism; In Vitro; Individual; Inherited; Investigation; Laboratories; Laboratory Study; Lead; Length; Link; Low Prevalence; Measurement; Menorrhagia; Modification; Molecular; Molecular Abnormality; Mutate; Mutation; Nuclear Family; Other Genetics; Patients; Penetrance; Peptide Hydrolases; Phenotype; Physicians; Physiological; Plasma; Play; Prevalence Study; Process; Production; Proteins; Proteolysis; Protocols documentation; Recording of previous events; Relative (related person); Reporting; Research; Research Design; Research Personnel; Resort; Ristocetin; Role; Sampling; Screening procedure; Sequence Determination; Series; Severity of illness; Societies; Structure; Symptoms; System; Testing; Thrombosis; United States; Variant; Woman; base; blood group; clinical Diagnosis; comparative; design; globular protein; improved; in vivo; member; mutant; non-genetic; proband; racial and ethnic; shear stress; von Willebrand Disease; von Willebrand Factor

Project 1 will consist of a multi-institutional study of patients with von Willebrand disease and will perform a clinical assessment of these patients and 1) determine the linkage of low or abnormal VWF within families, 2) determine genetic mutations in the VWF gene that could result in these clinical manifestations or 3) identify the frequency of inheritable abnormal VWF caused by other genetic loci residing outside the VWF gene. Candidate genes that might cause this will be identified through Projects 3 and 4. When genetic VWF mutations are identified, Project 2 will express the mutant VWF and define the underlying pathophysiologic mechanism(s) in vitro and in vivo. Aim 1 will identify the frequency of VWF gene mutations in patients with the clinical diagnosis of VWD and correlate these to their laboratory testing as well as a clinical scoring system that is a modification of the one used in the European Union Study of VWD. It will determine if the spectrum of genetic mutations causing type 3 VWD (or it's heterozygous carriers differs from those mutations identified in VWFlinked type 1 VWD. Aim 2 will identify the mutations causing variant, type 2 VWD and determine the penetrance of clinical bleeding symptoms with the scoring system used to study type 1 patients. Clinical laboratory phenotyping will be performed to contrast the degree of abnormality in affected, linked family members. Aim 3 will determine the frequency of VWD that is caused by increased plasma clearance that can be detected by comparing plasma levels of the VWF propeptide (VWFpp) to VWF, identifying clearance of VWF released by DDAVP, and will determine the differences between these in blood group O and non-O individuals. Since VWD has been reported to be common in women with menorrhagia, Aim 4 will study the prevalence of low or abnormal VWF in these women compared to age-matched controls. In those with reduced or abnormal VWF, we will determine if the mutation rate and distribution of mutations is similar to those identified in type 1 VWD. Project 1 will lead to a greater understanding of the scope and impact of clinical VWD and its ability to be detected in the clinical and research laboratory.

项目 1 将包括对冯·维勒布兰德病患者的多机构研究，并将进行 对这些患者进行临床评估，1) 确定家族内 VWF 低或异常的联系，2) 确定 VWF 基因中可能导致这些临床表现的基因突变，或 3) 确定 由 VWF 基因之外的其他基因位点引起的遗传性异常 VWF 的频率。候选人 可能导致这种情况的基因将通过项目 3 和 4 进行鉴定。当 VWF 基因突变发生时 确定后，项目 2 将表达突变 VWF 并定义潜在的病理生理机制 体外和体内。目标 1 将确定临床患者中 VWF 基因突变的频率 VWD 的诊断并将其与实验室测试以及临床评分系统相关联 欧盟 VWD 研究中使用的修改。它将确定遗传谱是否 导致 3 型 VWD 的突变（或其杂合携带者与 VWFlinked 中发现的突变不同） 1型VWD。目标 2 将识别导致变体、2 型 VWD 的突变并确定 临床出血症状的外显率与用于研究 1 型患者的评分系统。临床 将进行实验室表型分析，以对比受影响的、有关联的家族的异常程度 成员。目标 3 将确定由血浆清除率增加引起的 VWD 频率，可通过 通过比较 VWF 前肽 (VWFpp) 与 VWF 的血浆水平来检测，确定 VWF 的清除情况 由 DDAVP 释放，并将确定 O 型血和非 O 型血个体之间的差异。 据报道，VWD 在月经过多的女性中很常见，因此目标 4 将研究 VWD 的患病率 与年龄匹配的对照相比，这些女性的 VWF 较低或异常。对于那些减少或异常的人 VWF，我们将确定突变率和突变分布是否与 1 型中鉴定的类似 VWD。项目 1 将加深对临床 VWD 的范围和影响及其能力的了解 在临床和研究实验室进行检测。