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.

项目摘要 深静脉血栓形成（DVT）和继发性肺栓塞影响0.1-0.2%的 每年造成60，000 - 100，000人死亡， 类似于心肌梗塞。1856年病理学家鲁道夫·魏尔啸 DVT发病机制中静脉血流量的变化，但分子和 血液动力学变化如何驱动DVT发病机制的遗传基础尚未被 目前的治疗仅限于预防性措施，以增加静脉 血流和全身抗凝。我们最近证明， 内皮GATA 2-FOXC 2-PROX 1转录途径被振荡或 反向流动，并需要刺激静脉和淋巴阀的形成。 我们的初步研究表明，静脉瓣膜周围的内皮细胞， 经历类似的振荡流表达GATA 2-FOXC 2-PROX 1转录 程序与以低vWF、高vWF、高vWF为标志的强抗凝表型相关， EPCR、高TM和高TFPI表达。这种转录程序的丢失 由改变的静脉流动或瓣膜周围EC中的遗传缺失赋予的血栓 静脉瓣周围形成。我们假设内皮细胞GATA 2-FOXC 2- 振荡流刺激的PROX 1表达维持抗凝内皮细胞 表型需要防止DVT形成。本提案将检验这一假设 使用遗传学方法的组合来专门删除 小鼠瓣膜周围内皮细胞中的GATA 2/FOXC 2/PROX 1通路，外科手术 减少小鼠静脉血流量的方法，以及组织学和生理学研究 以测试这种机制是否在人类中保守， 在DVT发病过程中丢失。这些研究有望建立一个遗传和 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