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Structural origin of fibrin clot mechanical properties

纤维蛋白凝块机械性能的结构起源

基本信息

批准号：
8267014
负责人：
JOHN W WEISEL
金额：
$ 38.88万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267014
关键词：
Appearance Applications Grants Atomic Force Microscopy Behavior Beryllium Biochemical Biocompatible Materials Biological Biomechanics Biomedical Research Biopolymers Blood Clot Blood Platelets Blood coagulation Blood flow Bundling Caliber Characteristics Clinical Coagulation Process Coronary artery Custom DNA Sequence Rearrangement Diagnosis Disease Elasticity Engineering Event Factor XIII Fiber Fibrin Fibrinogen Fluorescence Microscopy Health Hemorrhage Hemostatic function Impaired wound healing Individual Lead Measurement Measures Mechanical Stress Mechanics Methods Microscopic Modeling Molecular Molecular Analysis Molecular Structure Motion Myocardial Infarction Nature Patients Pattern Pharmacia brand of estropipate Physiological Plasma Polymers Property Prophylactic treatment Proteins Recombinants Relative (related person)Research Roentgen Rays Rupture Scanning Probe Microscopes Scanning Transmission Electron Microscopy Procedures Shapes Side Spectroscopy, Fourier Transform Infrared Stress Stretching Stroke Structure Surface System Techniques Testing Thrombin Thromboembolism Thrombosis Thrombus Time Vacuum Variant Wound Healing X ray diffraction analysis X-Ray Diffraction base clinically significant flexibility in vivo laser tweezer magnetic field mechanical behavior molecular domain multi-scale modeling nano nanoscale network models protein function research study single molecule theories

项目摘要

DESCRIPTION (provided by applicant): Although we know a great deal about the structure and many aspects of the functions of fibrin(ogen), we still know very little about the microscopic and molecular structural origins of the fibrin clot's mechanical properties. Since blood clotting in vivo is essentially a mechanical task, it is important to determine how clots and thrombi respond to mechanical stresses imposed by highly dynamic conditions, such as blood flow, stretching a vessel wall and wounds, etc. In the research proposed in this application, the structural basis of the elastic and viscous properties of fibrin biopolymers is going to be examined using an integrated approach, which includes different levels of analysis, the molecular level, individual fibers, fiber network, and the whole clot, and the determination of relationships between these different levels of structure. Specific Aim 1: At the nano scale, the micromechanics of fibrin(ogen) will be examined by forced unfolding of its molecular domains during pulling on engineered oligomeric constructs by single-molecule atomic force microscopy, and observing the structural transitions by wide angle X-ray diffraction or Fourier Transform infrared spectroscopy while stretching of fibrin clots. Specific Aim 2: At the microscopic scale, the mechanical properties of fibers will be studied by bending and stretching of individual fibers in different clots by atomic force microscopy or optical tweezers, and investigating potential elongation of molecules and molecular packing by means of the small angle X-ray diffraction pattern during stretching of magnetically oriented clots. Structural changes in fiber network rearrangement, such as alignment and bundling of fibers, with clot deformation will be examined by scanning and transmission electron microscopy. Specific Aim 3: At the macro level, the viscoelastic properties of a variety of whole clots and thrombi extracted from patients' coronary arteries will be measured using rotational and extensional rheometry and correlated with parameters quantifying clot and thrombi structure. To build a general theory of the structural origin of clot mechanics, we will develop constitutive models that take advantage of the quantitative information derived from experiments at all the structural levels. In biological terms, fibrin(ogen) may represent one of the first clear examples of the physiological function of forced protein unfolding. On the clinical side, understanding mechanisms of fibrin deformation would explain and predict clot behavior in different physiological or pathophysiological conditions related to hemostasis, thrombosis, and wound healing and may lead to new methods of prophylaxis, diagnosis, or treatment. The proposal represents a new and promising field of biomedical research, namely biomechanics of hemostasis and thrombosis. PUBLIC HEALTH RELEVANCE: The focus of the research proposed in this grant application will be on the characteristics of fibrin(ogen) molecules, fibers, and networks that give rise to blood clot mechanical properties and the determination of relationships between these different levels of structure, using a variety of biophysical techniques. The results of these studies have clinical significance since clots with low elasticity and high plasticity tend to be associated with bleeding, while very stiff clots have been associated with thrombosis and thromboembolism, which cause heart attacks and strokes. In biological terms, fibrin(ogen) may represent one of the first clear examples of the physiological function of protein unfolding. More generally, this research involves the determination of relationships between molecular structure and the mechanical properties of a remarkable biological material, the blood clot.

描述（由申请人提供）：尽管我们对纤维蛋白（原）的结构和功能的许多方面了解很多，但我们对纤维蛋白凝块的机械性质的微观和分子结构来源仍然知之甚少。由于体内血液凝固基本上是一项机械任务，因此确定凝块和血栓如何响应由高度动态条件（例如血流、拉伸血管壁和伤口等）施加的机械应力是重要的。在本申请中提出的研究中，将使用综合方法来检查纤维蛋白生物聚合物的弹性和粘性性质的结构基础，其包括不同水平的分析、分子水平、单个纤维、纤维网络和整个凝块，以及确定这些不同水平的结构之间的关系。具体目标1：在纳米尺度上，纤维蛋白（原）的微观力学将通过单分子原子力显微镜在拉动工程化寡聚体构建体期间强制展开其分子结构域来检查，并通过广角X射线衍射或傅立叶变换红外光谱观察结构转变，同时拉伸纤维蛋白凝块。具体目标二：在微观尺度上，纤维的机械性能将通过原子力显微镜或光镊弯曲和拉伸不同凝块中的单个纤维来研究，并通过在磁取向凝块拉伸期间的小角度X射线衍射图案来研究分子和分子堆积的潜在伸长。将通过扫描和透射电子显微镜检查纤维网络重排的结构变化，例如纤维的排列和成束，以及凝块变形。具体目标3：在宏观水平上，将使用旋转和拉伸流变仪测量从患者冠状动脉提取的各种完整凝块和血栓的粘弹性，并将其与量化凝块和血栓结构的参数相关联。为了建立一个一般理论的血块力学的结构起源，我们将开发本构模型，利用来自实验的定量信息，在所有的结构水平。在生物学术语中，纤维蛋白（原）可能代表强制蛋白质解折叠的生理功能的第一个明确的例子之一。在临床方面，理解纤维蛋白变形的机制将解释和预测与止血、血栓形成和伤口愈合相关的不同生理或病理生理条件下的凝块行为，并可能导致新的预防、诊断或治疗方法。该提案代表了生物医学研究的一个新的和有前途的领域，即止血和血栓形成的生物力学。公共卫生相关性：在这项资助申请中提出的研究重点将是纤维蛋白（原）分子，纤维和网络的特性，这些特性会导致血凝块的机械特性，并使用各种生物物理技术确定这些不同层次的结构之间的关系。这些研究的结果具有临床意义，因为具有低弹性和高可塑性的凝块往往与出血有关，而非常坚硬的凝块与血栓形成和血栓栓塞有关，这会导致心脏病发作和中风。在生物学术语中，纤维蛋白（原）可能代表蛋白质解折叠的生理功能的第一个明确的例子之一。更一般地说，这项研究涉及确定分子结构与一种非凡的生物材料（血凝块）的机械特性之间的关系。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intracellular origin and ultrastructure of platelet-derived microparticles.

DOI：
10.1111/jth.13745
发表时间：
2017-08
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
0
作者：
Ponomareva AA;Nevzorova TA;Mordakhanova ER;Andrianova IA;Rauova L;Litvinov RI;Weisel JW
通讯作者：
Weisel JW

Conformational Flexibility and Self-Association of Fibrinogen in Concentrated Solutions.

DOI：
10.1021/acs.jpcb.7b05654
发表时间：
2017-08
期刊：
The journal of physical chemistry. B
影响因子：
0
作者：
Y. Zuev;R. Litvinov;A. E. Sitnitsky;B. Idiyatullin;D. R. Bakirova;D. Galanakis;A. Zhmurov;V. Barsegov;J. Weisel
通讯作者：
Y. Zuev;R. Litvinov;A. E. Sitnitsky;B. Idiyatullin;D. R. Bakirova;D. Galanakis;A. Zhmurov;V. Barsegov;J. Weisel

Quantitative structural mechanobiology of platelet-driven blood clot contraction.

DOI：
10.1038/s41467-017-00885-x
发表时间：
2017-11-02
期刊：
Nature communications
影响因子：
16.6
作者：
Kim OV;Litvinov RI;Alber MS;Weisel JW
通讯作者：
Weisel JW

Single-Molecule Interactions of a Monoclonal Anti-DNA Antibody with DNA.

DOI：
10.1007/s12668-016-0303-0
发表时间：
2017-03
期刊：
BioNanoScience
影响因子：
3
作者：
Nevzorova TA;Zhao Q;Lomakin YA;Ponomareva AA;Mukhitov AR;Purohit PK;Weisel JW;Litvinov RI
通讯作者：
Litvinov RI

Fibrin mechanical properties and their structural origins.