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（由应用提供）：在过去的几年中，生物医学研究，止血和血栓形成的生物力学领域一直在迅速发展。纤维蛋白的机械性能是自然可变的，并且在很大程度上确定了切片的截面出血或导致血栓形成或出血，这使它们成为理想的治疗靶标。在此应用中，在物理相关的纤维蛋白变形期间，纤维蛋白力学将在复杂水平上增加，包括单个分子，纤维蛋白低聚物和整个纤维蛋白布以及离体血栓形成。基于最先进的生物物理技术，例如基于单分子光学诱捕的力光谱，广角X射线散射，傅立叶近变频谱，在近距离示意力，高分辨率的漫画，概要循环综合，概述，将使用基于最先进的生物物理技术的独特，综合技术，在基于单分子的力X射线散射，概述的循环层次，符合型号的循环液，将使用基于最新的生物物理技术的结构基础进行研究分子动力学模拟和多尺度建模。在特定的目标1中，分子水平的纤维蛋白的结构过渡 由机械力诱导的将研究。了解盘绕线圈，αc区域和γ-结节的展开将定义由于血流，凝块回缩和伤口拉伸而导致体内发生的分子变化。盘绕螺旋中的α-螺旋向β--折叠过渡是纤维蛋白机械的重要机制，并且可能用于临床目的。 αC聚合物的拉直和 - 结节的展开也在纤维蛋白机械性能中起主要作用。在特定的目标2中，A的纳米力学：将纤维蛋白结合在一起的旋钮键将在单分子水平上进行研究。初步数据显示在a：a 债券暴露了违反直觉的“捕获”键行为，这意味着键的强度随着力的增加而增加。这个新颖的发现是进一步深入研究的基础，因为 它对生物分子相互作用和潜在生理意义的领域的一般重要性。使用新方法，结合 - 解开相关光谱，我们开发了我们将广泛表征单个A形成和解离的二维动力学和热力学。在特定的目标3中，将研究临床意义的云和血栓的机械性能，并从分子和显微镜水平到体内形成的增长复杂的宏观结构进行逻辑发展。筛选可能稳定或破坏稳定的化学物质和结构修饰 将进行纤维蛋白分子结构域，以揭示用于治疗目的的纤维蛋白机械性能的潜在调节剂。这些研究将通过导致新的结构和基于机械的方法来预防和治疗出血和血栓形成，从而促进止血和血栓形成领域。