Natural Variation in VWF and FVIII

VWF 和 FVIII 的自然变异

• 批准号: 8458957
• 负责人: Jill Marie Johnsen
• 金额: $ 13.35万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458957
• 关键词: ABO blood group system; Accounting; Antigens; Attenuated; Binding; Biological Assay; Biological Markers; Biology; Blood Circulation; Blood Coagulation Disorders; Blood Platelets; Blood donor; Blood typing procedure; Characteristics; Chronic Disease; Clinical Trials; Coagulation Process; DNA Sequence; Detection; Development; Disease; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Factor VIII; Financial cost; Foundations; Future; Gel; Gender; Healthcare Systems; Hemophilia A; Hemorrhage; Hemostatic Agents; Hemostatic function; Human; Inherited; Investigation; Laboratories; Lead; Ligands; Link; Lymphocyte; Measures; Molecular; Molecular Conformation; Morbidity - disease rate; Myocardial Infarction; Nature; Pathogenesis; Plasma; Population; Proteins; Residual state; Risk; Sampling; Stroke; Structure; Subgroup; Surface; System; Testing; Therapeutic Agents; Thromboembolism; Thrombosis; Variant; Venous; Whole Blood; Work; Y Chromosome; bacterial H antigen; blood group; design; innovation; insight; mortality; nanobodies; novel; prognostic; repository; treatment strategy; von Willebrand Disease; von Willebrand Factor

DESCRIPTION (provided by applicant): Levels of the critical plasma clotting proteins von Willebrand Factor (VWF) and Factor VIII (FVIII) are widely variable in humans. High levels of VWF and FVIII confer an increased risk of thrombosis, while low levels are associated with bleeding. The wide range of quantitative variation in VWF has been well described, but the degree and nature of functional variation in VWF and its interaction with FVIII is less clear. We hypothesize that VWF is both quantitatively and qualitatively variable. There is some evidence that natural variation in the VWF molecule influences survival of VWF in circulation and/or may shift the nature of interactions with two of its key ligands, platelets and FVIII. We propose to study the natural variation of VWF in samples from 500 subjects from the General Lymphocyte and Plasma Repository (GLPR) by measuring attributes associated with the major hemostatic functions of VWF. We will evaluate parameters related to VWF survival, VWF platelet binding, VWF multimeric structure, and the interaction of VWF with FVIII. The known VWF modifiers ABO blood group and gender will be assessed and accounted for in the analysis. We will test a novel hypothesis that the FVIII/VWF ratio is normally variable, and pursue a new investigation into the influence of the blood group H antigen system on VWF molecular characteristics. The results of this study should lend new insights into the biology of VWF and FVIII, and may lead to the development of novel prognostic coagulation biomarkers for study in future clinical trials. Furthermore, this work could provide the foundation for the design or optimization of therapeutic agents in bleeding and clotting disorders.

性状（由申请方提供）：关键血浆凝血蛋白血管性血友病因子（VWF）和因子VIII（FVIII）的水平在人体内存在很大差异。高水平的VWF和FVIII会增加血栓形成的风险，而低水平则与出血有关。VWF的广泛的定量变异已经得到了很好的描述，但VWF的功能变异的程度和性质及其与FVIII的相互作用尚不清楚。我们假设VWF是定量和定性变量。有一些证据表明，VWF分子的自然变异影响VWF在循环中的存活和/或可能改变与其两个关键配体血小板和FVIII相互作用的性质。我们建议通过测量与VWF主要止血功能相关的属性，研究来自一般淋巴细胞和血浆储存库（GLPR）的500例受试者样本中VWF的自然变化。我们将评估与VWF存活、VWF血小板结合、VWF多聚体结构以及VWF与FVIII相互作用相关的参数。将评估已知的VWF修饰剂ABO血型和性别，并在分析中说明。我们将测试一个新的假设，即FVIII/VWF的比例是正常的变量，并追求一个新的调查血型H抗原系统对VWF分子特征的影响。这项研究的结果将为VWF和FVIII的生物学提供新的见解，并可能导致新的预后凝血生物标志物的开发，用于未来的临床试验研究。此外，这项工作可以为出血和凝血障碍的治疗药物的设计或优化提供基础。