Fibrin Structures and Lung Injury

纤维蛋白结构和肺损伤

基本信息

批准号：
8265599
负责人：
HARRY ISCHIROPOULOS
金额：
$ 40.92万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8265599
关键词：
Accounting Acute Acute Lung Injury Address Animal Model Antifibrinolytic Agents Architecture Biochemical Biological Biological Markers Blood Coagulation Disorders Blood Platelets Blood Vessels Cardiovascular system Cessation of life Clinical Clinical Data Clinical Trials Coagulants Coagulation Process Coronary Arteriosclerosis Cytolysis Data Deep Vein Thrombosis Deposition Development Diagnosis Diagnostic Embolism Enzyme-Linked Immunosorbent Assay Epidemiology Evaluation Event Failure Fibrin Fibrinogen Fibrinolysis Fibrinolysis Pathway Functional disorder Future Health Hemostatic Agents Hemostatic function Heparin Human Inflammation Inflammatory Injury Knockout Mice Life Ligands Link Lung Mass Spectrum Analysis Measures Mechanics Mediator of activation protein Methodology Modeling Modification Molecular Molecular Target Morbidity - disease rate Mus Nested Case-Control Study Nitrates Nitric Oxide Nitric Oxide Synthase Organ Pathology Pathway interactions Patients Pediatric Hospitals Pennsylvania Philadelphia Plasminogen Inactivators Positioning Attribute Property Publishing Pulmonary Circulation Pulmonary Embolism Pulmonary Thromboembolism Recovery Recurrence Reporting Research Resistance Resolution Rheology Risk Risk Factors Sampling Scanning Electron Microscopy Sepsis Severities Source Specific qualifier value Structure Surface Syndrome Testing Thromboembolism Thrombomodulin Thromboplastin Thrombus Time Translating Trauma Treatment Efficacy Tyrosine United States Universities Variant Vascular Diseases Vascular Endothelium Venous Work activated Protein C base bench to bedside cardiovascular risk factor cigarette smoking design high risk improved in vivo insight lung injury mortality mouse model novel prognostic programs receptor reconstitution

项目摘要

DESCRIPTION (provided by applicant): Activation of the coagulation cascade converts soluble fibrinogen to insoluble fibrin, which polymerizes to produce, along with platelets, the haemostatic clot. Whereas the normal activation of the coagulation cascade is essential for life, inappropriate activation or failure to dissolve deposited fibrin in a timely manner may result in fibrin-dependent organ pathology. Indeed pathologically induced thrombogenesis produces venous thromboembolism (VTE), a major cause of morbidity and mortality in the USA. The pulmonary vascular compartment is a major target for VTE and other clinical syndromes characterized by fibrin deposition. However, it is unclear if the structure and mechanical properties of fibrin influences the severity of VTE and pulmonary complications. Recent studies have provided provocative new insights regarding the presence of fibrin structures with altered architecture and mechanical properties in subjects with coronary artery disease. These new findings provide mechanistic associations with the previously documented epidemiological findings between fibrinogen/fibrin and risk of cardiovascular complications. Despite similar epidemiological associations, the functional consequences and contributions of fibrin networks for the risk of developing VTE and pulmonary dysfunction remain untested. Therefore we propose that abnormal fibrin structures that are resistant to fibrinolysis induce pulmonary vascular abnormalities confer a high risk for VTE and acute lung injury. This hypothesis will be tested by: 1) Quantifying fibrin-clot turbidity, fibrin structure, fibrinolytic resistance and levels of oxidatively-modified fibrinogen in patients with clinically documented deep venous thrombosis. 2) Testing the functional consequences of thromboemboli generated from fibrinogen isolated from clinically documented DVT subjects in a mouse model of pulmonary thromboemboli challenge. 3) Ascertaining the functional consequences of fibrin generated in vivo from fibrinogen isolated from clinically documented DVT subjects in a mouse model of acute thromboembolism. Collectively these mouse models aim to evaluate for the first time the influence of variant fibrin structures in deriving pulmonary vascular complications. Successful completion of these specific aims will provide a systematic study of the biochemical and biophysical properties of fibrin clots in subjects at risk for acute thromboembolism and explore the potential biological consequences of altered fibrin assemblies in vivo.

描述（由申请人提供）：凝血级联反应的激活将可溶性纤维蛋白原转化为不溶性纤维蛋白，该纤维蛋白与血小板一起产生聚合物，并与血小板一起产生止血凝块。尽管凝结级联反应的正常激活对生命至关重要，但不适当的激活或无法及时溶解纤维蛋白的及时激活可能会导致纤维蛋白依赖性器官病理学。确实，病理诱导的血栓形成会产生静脉血栓栓塞（VTE），这是美国发病率和死亡率的主要原因。肺血管室是以纤维蛋白沉积为特征的VTE和其他临床综合征的主要靶标。但是，尚不清楚纤维蛋白的结构和机械性能是否影响VTE和肺部并发症的严重程度。最近的研究提供了有关冠状动脉疾病受试者的结构和机械性能改变的纤维蛋白结构的挑衅性新见解。这些新发现提供了机械性关联，并具有先前记录的纤维蛋白原/纤维蛋白和心血管并发症风险之间的流行病学发现。尽管相似的流行病学关联，但纤维蛋白网络对发展VTE和肺部功能障碍的风险的功能后果和贡献仍未受过测试。因此，我们提出，抗纤维蛋白溶解性的异常纤维蛋白结构诱导肺血管异常赋予VTE和急性肺损伤的高风险。该假设将通过：1）量化临床记录的深静脉血栓形成患者的纤维蛋白 - 凝集浊度，纤维蛋白结构，纤维蛋白耐药性和氧化性纤维蛋白原的水平。 2）测试由肺血栓症挑战小鼠模型中从临床记录的DVT受试者中分离出的纤维蛋白原产生的血栓栓塞的功能后果。 3）确定从急性血栓栓塞小鼠模型中从临床记录的DVT受试者中分离出的纤维蛋白原产生的纤维蛋白的功能后果。这些小鼠模型旨在首次评估变异纤维蛋白结构在推导肺血管并发症中的影响。这些特定目标的成功完成将对纤维蛋白血块的生化和生物物理特性进行系统研究，以急性血栓栓塞风险，并探索体内改变纤维蛋白组件的潜在生物学后果。