Structural origin of fibrin clot mechanical properties

纤维蛋白凝块机械性能的结构起源

• 批准号: 8903542
• 负责人: JOHN W WEISEL
• 金额: $ 40.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903542
• 关键词: Affinity; Angioplasty; Applications Grants; Atomic Force Microscopy; Behavior; Binding; Biocompatible Materials; Biomechanics; Biomedical Research; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Characteristics; Chemicals; Clinical; Clot retraction; Coagulation Process; Complex; Confocal Microscopy; Data; Dissociation; Elasticity; Electron Microscopy; Exhibits; Fiber; Fibrin; Fibrinogen; Health; Hemorrhage; Hemostatic Agents; Hemostatic function; Human; Individual; Kinetics; Lateral; Lead; Length; Lipoproteins; Maps; Measures; Mechanics; Microscopic; Modeling; Modification; Molecular; Molecular Structure; Mutation; Myocardial Infarction; Nodule; Obstruction; Outcome; Pharmacia brand of estropipate; Physiological; Plasma; Plasma Proteins; Play; Polymers; Property; Proteins; Reaction; Recombinants; Research; Resolution; Roentgen Rays; Role; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Stretching; Stroke; Structure; Surface; Therapeutic; Therapeutic Embolization; Thermodynamics; Thromboembolism; Thrombosis; Thrombus; Venous; Wit; base; biophysical techniques; clinically significant; comparative; computerized; conformational conversion; crosslink; in vivo; inhibitor/antagonist; insight; molecular domain; molecular dynamics; multi-scale modeling; mutant; nanomechanics; network models; new therapeutic target; novel; novel strategies; optical traps; polymerization; prevent; reconstruction; response; screening; simulation; single molecule; therapeutic target; thrombolysis; two-dimensional; wound

DESCRIPTION (provided by applicant): A new field of biomedical research, biomechanics of hemostasis and thrombosis, has been quickly developing over the past few years. The mechanical properties of fibrin are naturally variable and largely determine whether clots stanch bleeding, or lead to thrombosis or hemorrhage, and this makes them a desirable therapeutic target. In this application, fibrin mechanics will be studied with respect to structural changes during physiologically relevant fibrin deformations at increasing levels of complexity, including individual molecules, fibrin oligomers, and whole fibrin clots as well as ex vivo thrombi. The structural basis of the viscoelastic properties of fibrin is going to be examined using a uniquely broad, integrated approach based on state-of-the- art biophysical techniques, such as single-molecule optical trap-based force spectroscopy, wide angle X-ray scattering, Fourier Transform infrared spectroscopy, high-resolution rheometry, atomic force microscopy, confocal and electron microscopy, combined with computational molecular dynamics simulations and multiscale modeling. In Specific Aim 1, the structural transitions in fibrin at the molecular level induced by mechanical force will be studied. Understanding of the unfolding of the coiled-coils, αC regions, and γ-nodules will define the molecular changes that occur in vivo as a result of blood flow, clot retraction, and wound stretching. The α-helix to β-sheet transition in the coiled-coils is an important mechanism of fibrin mechanics and potentially tunable for clinical purposes. Straightening of the αC polymers and unfolding of the ?-nodules also play major roles in fibrin mechanical properties. In Specific Aim 2, nanomechanics of the A:a knob-hole bonds that hold fibrin together will be studied at the single-molecule level. Preliminary data show that at the A:a bonds exhibit counterintuitive "catch" bond behavior, meaning that the strength of the bond increases with increasing force. This novel finding is a basis for further in depth studies because of its general importance for the field of biomolecular interactions and potential physiological significance. Using a new approach, Binding- Unbinding Correlation Spectroscopy, that we developed we will extensively characterize the two-dimensional kinetics and thermodynamics of formation and dissociation of single A:a bonds. In Specific Aim 3, mechanical properties of clinically significant clots and thrombi will be studied, with a logical progression from the molecular and microscopic levels to increasingly complex macroscopic structures formed in vivo. Screening of chemicals and structural modifications that potentially stabilize or destabilize fibrin molecular domains will be performed to reveal potential modulators of fibrin mechanical properties for therapeutic purposes. These studies would advance the field of hemostasis and thrombosis by leading to new structure- and mechanics-based approaches to prevent and treat bleeding and thrombosis.

描述（由申请人提供）：止血和血栓形成生物力学是生物医学研究的一个新领域，近年来发展迅速。纤维蛋白的机械特性是自然可变的，在很大程度上决定了凝块是止血，还是导致血栓形成或出血，这使它们成为理想的治疗靶点。在这个应用中，纤维蛋白力学将研究在生理相关纤维蛋白变形过程中的结构变化，包括单个分子、纤维蛋白低聚物、整个纤维蛋白凝块以及体外血栓。纤维蛋白粘弹性特性的结构基础将通过一种独特而广泛的综合方法进行研究，该方法基于最先进的生物物理技术，如基于单分子光阱的力谱，广角x射线散射，傅立叶变换红外光谱，高分辨率流变学，原子力显微镜，共聚焦和电子显微镜，结合计算分子动力学模拟和多尺度建模。在Specific Aim 1中，纤维蛋白在分子水平上的结构转变