Human Translational Studies of Vascular Thrombosis and Inflammation

血栓形成表现为静脉血栓栓塞症、中风和心脏病发作，在美国是主要的死亡原因。尽管使用了抗血栓药物，这些患者中的许多人仍会发生血栓形成，这突显了科学和治疗进步的必要性，以降低心血管死亡率和发病率。包括我们在内的几个小组最近关于炎症和凝血交叉点的发现，重新引起了人们对支撑血栓形成和血管疾病的炎症机制的兴趣。为了更深入地了解疾病机制和治疗机会，我们利用临床和翻译工具来表征血管血栓炎症的临床表型和细胞和分子过程。使用多种互补的方法，结合人类、小鼠和临床前的体外/体外研究，我们以床边到工作台和工作台到床边的方法检查血管疾病。这些研究主要围绕以下几个项目展开：项目(1)：嘌呤能异常调节。具有遗传性或获得性嘌呤能信号功能障碍的患者有发生血管并发症的风险。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。调查还探索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在内的多个患者群体产生影响，这些患者可能会释放对血栓炎症的内源性刹车。项目(2)：自体炎症。我们先前发现炎性小体激活和白介素1β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性疾病患者的血液学和血管过程。 这些调查极有可能在科学和公共卫生方面带来有意义的进步。

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.