Molecular and genetic basis of deep venous thrombosis

深静脉血栓形成的分子和遗传学基础

基本信息

批准号：
10200879
负责人：
MARK L KAHN
金额：
$ 58.43万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-18 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200879
关键词：
ARNT gene Affect Alleles Anatomy Animals Anticoagulants Anticoagulation Blood Platelets Blood Vessels Blood coagulation Blood flow Cells Cessation of life Coagulation Process Data Deep Vein Thrombosis Disease Doppler Ultrasound Endothelial Cells Endothelium Environment F2R gene FOXC2 gene Factor IX Foundations Gene Expression Genes Genetic Genetic Transcription Health Histologic Hospitals Human Image Immobilization In Vitro Incidence Inflammation Injury Inpatients Knock-in Leg Link Measures Mechanics Molecular Molecular Genetics Mus Myocardial Infarction Operative Surgical Procedures Pathogenesis Pathologic Pathologist Pathway interactions Phenotype Physiological Physiology Population Posture Process Pulmonary Embolism Reporting Research Design Risk Factors Role Sinus Site Surgical Models TFPI Testing Thrombin Thrombophilia Thrombosis Thrombus Translating VWF gene Varicosity Veins Venous Venous Thrombosis Work activated protein C receptor design experience factor V Leiden genetic approach healthy volunteer hemodynamics human disease in vivo lymphatic valve mortality mouse model novel oscillatory blood flow prevent programs prophylactic response transcription factor

项目摘要

Project Summary Deep venous thrombosis (DVT) and secondary pulmonary embolism affect 0.1-0.2% of the population and cause 60,000-100,000 deaths annually, an incidence and mortality similar to that of myocardial infarction. In 1856 the pathologist Rudolph Virchow implicated changes in venous blood flow in DVT pathogenesis, but a molecular and genetic basis for how hemodynamic changes drive DVT pathogenesis has not been identified, and present therapy is restricted to prophylactic measures to augment venous blood flow and systemic anticoagulation. We have recently demonstrated that the endothelial GATA2-FOXC2-PROX1 transcriptional pathway is activated by oscillatory or reversing flow and required to stimulate the formation of venous and lymphatic valves. Our preliminary studies demonstrate that endothelial cells around venous valves that experience similar oscillatory flow express the GATA2-FOXC2-PROX1 transcriptional program in association with a strong anti-coagulant phenotype marked by low vWF, high EPCR, high TM, and high TFPI expression. Loss of this transcriptional program conferred by altered venous flow or genetic deletion in peri-valvular ECs results in clot formation around the venous valve. We hypothesize that endothelial GATA2-FOXC2- PROX1 expression stimulated by oscillatory flow maintains an anticoagulant endothelial phenotype required to prevent DVT formation. This proposal will test this hypothesis using a combination of genetic approaches to specifically delete the GATA2/FOXC2/PROX1 pathway in mouse peri-valvular endothelial cells, surgical approaches to reduce venous flow in the mouse, and histologic and physiologic studies of human venous valves to test whether this mechanism is conserved in humans and lost during DVT pathogenesis. These studies are expected to establish a genetic and molecular mechanism for DVT pathogenesis that will serve as the foundation for novel mechanical and molecular therapies.

项目概要深静脉血栓 (DVT) 和继发性肺栓塞影响 0.1-0.2% 每年导致 60,000-100,000 人死亡，发病率和死亡率与心肌梗塞相似。 1856 年，病理学家鲁道夫·维尔肖 (Rudolph Virchow) DVT 发病机制中涉及静脉血流的变化，但分子和血流动力学变化如何驱动 DVT 发病机制的遗传基础尚未明确已确定，目前的治疗仅限于增加静脉血的预防措施血流量和全身抗凝。我们最近证明了内皮 GATA2-FOXC2-PROX1 转录途径由振荡或逆转血流并需要刺激静脉和淋巴瓣膜的形成。我们的初步研究表明，静脉瓣周围的内皮细胞经历类似的振荡流表达 GATA2-FOXC2-PROX1 转录与强抗凝表型相关的程序，其特征是低 vWF、高 EPCR、高 TM 和高 TFPI 表达。该转录程序的丢失静脉血流改变或瓣膜周围 EC 基因缺失导致血栓静脉瓣周围形成。我们假设内皮 GATA2-FOXC2- 振荡流刺激的 PROX1 表达维持内皮细胞的抗凝预防 DVT 形成所需的表型。该提案将检验这一假设使用遗传方法的组合来专门删除小鼠瓣膜周围内皮细胞中的 GATA2/FOXC2/PROX1 通路，手术减少小鼠静脉流量的方法以及组织学和生理学研究人类静脉瓣膜以测试这种机制在人类中是否保守 DVT 发病过程中丢失。这些研究预计将建立一个遗传和 DVT发病机制的分子机制将作为新的基础机械和分子疗法。