Molecular and genetic basis of deep venous thrombosis

深静脉血栓形成的分子和遗传学基础

• 批准号: 10460687
• 负责人: MARK L KAHN
• 金额: $ 35.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460687
• 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

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 程序与强抗凝表型相关，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。

项目成果

Defects in vein valve PROX1/FOXC2 antithrombotic pathway in endothelial cells drive the hypercoagulable state induced by trauma and critical illness.

内皮细胞中静脉瓣膜 PROX1/FOXC2 抗血栓通路的缺陷导致创伤和危重疾病引起的高凝状态。

• DOI: 10.1097/ta.0000000000003945
• 发表时间: 2023
• 期刊: The journal of trauma and acute care surgery
• 作者: Hoofnagle,MarkH;Hess,Annie;Nalugo,Margaret;Ghosh,Sarbani;Hughes,Shin-Wen;Fuchs,Anja;Welsh,JohnD;Kahn,MarkL;Bochicchio,GrantV;Randolph,GwendalynJ;Leonard,JenniferM;Turnbull,IsaiahR
• 通讯作者: Turnbull,IsaiahR