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Structure-Resolved Mechanistic Phenotyping of Von Willebrand Disease

冯维勒布兰德病的结构解析机制表型

基本信息

批准号：
10440371
负责人：
Matthew Auton
金额：
$ 42.99万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440371
关键词：
Address Adhesions Adhesives Affect Affinity Behavior Binding Binding Sites Biological Assay Blood Blood Coagulation Disorders Blood Platelets Blood flow Classification Clinical Data Detection Deuterium Diagnosis Diagnostic Disease Elements Fiber Functional disorder Genotype Goals Heart Diseases Hematological Disease Hemorrhage Hemostatic Agents Human Hydrogen Inherited Knowledge Label Lead Lung diseases Maps Mass Spectrum Analysis Measures Mechanics Methods Modeling Molecular Conformation Molecular Probes Mutation National Heart, Lung, and Blood Institute Pathologic Pathology Patient Care Patients Phenotype Physicians Plasma Prevalence Proteins Public Health Publishing Pyrimidine RNA Recombinants Recommendation Reporting Research Research Project Grants Resistance Resolution Rheology Role Severities Site Sleep Disorders Strategic vision Structure Testing Therapeutic Variant aptamer base blood rheology clinical diagnostics crosslink dimer disease diagnostic disease phenotype disease-causing mutation gain of function improved innovation loss of function new technology novel novel strategies nuclease platelet function predictive modeling prevent receptor response stoichiometry vascular injury von Willebrand Disease von Willebrand Factor

项目摘要

PROJECT SUMMARY: The primary hemostatic Von Willebrand Factor (vWF) sequesters platelets to arrest bleed- ing. Subject to the rheological shear of blood ﬂow, multimeric ﬁbers of vWF unravel exposing A1 domain hooks which capture platelets through the binding of platelet GPIb↵ receptors. Mutations within the A1 domain occur in all clinical classiﬁcations of von Willebrand disease (vWD), the most common inherited human bleeding dis- order, causing quantitative deﬁciencies of vWF in plasma and functional ﬂaws in platelet adhesion. The central paradigm of vWF function in disease is that mutations alter vWF's response to the rheological effects of blood ﬂow, but the the structural basis for how these mutations alter the mechanics of platelet adhesion to vWF is not understood. vWD mutations in A1 induce conformational changes that unfold local regions of the A1 domain structure in both type 2B (gain-of-function) and type 2M (loss-of-function) vWD phenotypes which are proposed to alter two previously unidentiﬁed A1-GPIB↵ binding sites The overall objective of this application is to decipher the role of A1 conformational disorder in GPIb↵ afﬁnity recognition. The central hypothesis is that the mechanism of dysfunction in vWD is not shear dependent, but rather, determined by the intrinsic conformational dynamics of these putative binding sites. To accomplish our objective, we will 1) identify the structural determinants for gain and loss of vWF-platelet function, 2) decipher the binding mechanism, and 3) develop novel technologies for the detection of pathological conformations of vWF in plasma. Our approach is innovative because it utilizes hydrogen-deuterium exchange and cross-linking mass spectrometry to attain high-resolution map of how struc- tural disorder predetermines GPIb↵ afﬁnity and it employs new RNA aptamer molecular probes that speciﬁcally bind and inhibit disordered conformations of the A1 domain within vWD patient plasma vWF. This research project addresses explicit needs, stated by the NHLBI, to enhance knowledge of vWD mechanisms, improve vWD diag- nostics, and it establishes novel methods for the phenotyping of vWD. The proposed studies are expected to enhance a basic scientiﬁc understanding of how vWD affects the linkage between folding and function of vWF and to improve interpretation of current diagnostics leading to better informed treatment recommendations and enhanced patient care.

项目总结：原发性止血药血管性血友病因子（vWF）可隔离血小板以阻止出血