Human Translational Studies of Vascular Thrombosis and Inflammation

血栓形成表现为静脉血栓栓塞、中风和心脏病发作，是美国死亡的主要原因。尽管使用了抗血栓药物，但仍有许多患者发生血栓形成，这突出表明需要科学和治疗进步来降低心血管死亡率和发病率。包括我们在内的几个研究小组最近发现了炎症和凝血的交叉点，这使得人们对血栓形成和血管疾病的炎症机制重新产生了兴趣。为了更深入地了解疾病机制和治疗机会，我们利用临床和转化工具来表征血管血栓炎症的临床表型、细胞和分子过程。通过结合人类、小鼠和临床前体外/离体研究的多种互补方法，我们从病床到工作台和从工作台到病床的方法检查血管疾病。这些都是围绕以下项目：项目(1)：嘌呤能失调。嘌呤能信号遗传或获得性功能障碍的患者有发生血管并发症的危险。我们的研究使用患者样本和临床相关性来探索与炎症和血栓信号相关的机制途径。调查还探讨了导致人类冠状病毒患者无节制炎症的过程。这些研究的结果将对多种患者群体产生影响，包括单基因疾病患者和接受癌症检查点抑制剂治疗的患者，这些患者可能会释放内源性的血栓炎症刹车。项目(2)：自体炎症。我们之前发现了炎性体活化和白细胞介素-1 β在静脉血栓形成中的作用。我们目前的研究旨在进一步阐明获得性和遗传性自身炎症疾病患者的血液学和血管过程。

Thrombosis presenting as venous thromboembolism, stroke, and heart attack is the leading cause of death in the United States. Many of these patients develop thrombosis despite use of antithrombotic drugs, highlighting a need for scientific and therapeutic advancements to reduce cardiovascular mortality and morbidity. Recent discoveries by several groups including ours about the intersection points of inflammation and coagulation have led to a resurgence of interest in the inflammatory mechanisms underpinning thrombosis and vascular disease. In pursuit of a deeper understanding of disease mechanisms and therapeutic opportunities, we utilize clinical and translational tools to characterize the clinical phenotype, and cellular and molecular processes of vascular thromboinflammation. Using multiple, complementary approaches that combine human, murine, and preclinical in vitro/ex vivo studies, we examine vascular disease in a bedside-to-bench and bench-to-bedside approach. These are centered around the following projects: Project (1): Purinergic Dysregulation. Patients with inherited or acquired dysfunction in purinergic signaling are at risk of developing vascular complications. Our studies use patient samples and clinical correlation to probe mechanistic pathways related to inflammatory and thrombotic signaling. Investigations also probe the processes that lead to unrestrained inflammation in patients with human coronavirus. The results of these studies will have implications for multiple patient populations including patients with monogenic disorders, and patients with treated with checkpoint inhibitors for cancer which may release the endogenous brakes on thromboinflammation. Project (2): Autoinflammation. We previously discovered the role of inflammasome activation and interleukin-1beta in venous thrombosis. Our current studies aim to further elucidate the hematologic and vascular processes in patients with acquired and inherited autoinflammatory disorders. These investigations are highly likely to lead to meaningful advances in science and public health.