Mechanistic Elucidation and Targeted Therapy of Platelet Dysfunction After Trauma

项目摘要：创伤是全球年轻人死亡的主要原因，据估计 仅在美国，每年的医疗费用就高达4000亿美元。创伤幸存者受苦 从器官衰竭和血栓栓塞症并发症的严重发病率，在很大程度上是由 部分是由于过度的炎症和恶性的凝血异常。缺乏理解 创伤后炎症和凝血障碍的调节机制呈现了一个重要的国际 健康问题，因为缺乏治疗目标严重限制了干预能力。因此， 了解创伤、炎症和凝血障碍之间的联系是制定策略的关键 帮助预防每年数以百万计的创伤幸存者的器官衰竭和发病率。我们的实验室最近 在理解一个潜在的联系方面取得了长足的进步。我们已经确定了通过密钥发出的信号 血小板上的先天免疫受体Toll样受体4(TLR4)在一定程度上导致了这两种疾病的过度 小鼠严重出血后的炎症和凝血障碍。这些发现是一项关键的早期进展 在这一领域，由于血小板既是止血的初始反应者，也是早期的关键效应细胞。 发炎炎症的开始。尽管有这些发现，触发这种血小板功能障碍的配体 通过TLR4是未知的。重要的是，已知严重创伤通过以下途径激活先天免疫系统 释放大量与危险相关的分子模式分子(湿气)。目前的建议 基于高迁移率基团框1(HMGB1)的假设，HMGB1是一种关键的阻尼剂，也是具有良好特性的TLR4 配体，由创伤后的血小板特异性释放，调节凝血功能异常 创伤后血栓形成部位相邻血小板旁分泌信号的观察 通过向中性粒细胞和其他炎症细胞发出信号而过度炎症。我们寻求解决3个问题 与这一假设相关的关键挑战。第一个涉及理解HMGB1通过什么机制 通过检测对关键的血小板黏附分子的影响来促进血栓形成。第二个考查 血小板HMGB1在中性粒细胞活化和中性粒细胞胞外陷阱(Net)产生中的作用 创伤后及血小板-HMGB1介导的净生成在急性肺损伤中的作用。最后，我们 提出使用我们最近获得专利的TLR4抑制剂的新颖和创新方法(美国 #9,072.760)和HMGB1抑制剂包装成模拟血小板的纳米给药载体，用于特定的药物 将活化的血小板定位于炎症和血栓形成的部位。

Project Summary: Trauma is the leading cause of death in young people worldwide and has an estimated annual healthcare cost of 400 billion dollars per year in the United States alone. Survivors of trauma suffer from severe morbidity in the form of organ failure and thromboembolic complications, which are driven, in large part, by excessive inflammation and a vicious cascade of coagulation abnormalities. The lack of understanding of the mechanisms that regulate inflammation and coagulopathy following trauma present a major international health problem, as the lack of therapeutic targets severely limits the ability to intervene. As such, understanding the link between trauma, inflammation and coagulopathy is the key to developing strategies to help prevent organ failure and morbidity in the millions of annual survivors of trauma. Our lab has recently made great strides towards understanding a potential link. We have identified that signalling through the key innate immune receptor, toll-like receptor 4 (TLR4) on platelets is responsible, in part, for both excessive inflammation and coagulopathy following severe hemorrhage in mice. These findings are a key early advance in the field, as platelets serve as both the initial responders in hemostasis but also as early, key effector cells in the initiation of inflammation. Despite these discoveries, the ligand that triggers this platelet `dysfunction' through TLR4 is unknown. Importantly, severe trauma is known to activate the innate immune system through a release of high quantities of danger associated molecular pattern molecules (DAMPs). The present proposal is based on the hypothesis that high-mobility group box 1 (HMGB1), a key DAMP and well characterized TLR4 ligand, is released specifically by platelets following trauma and regulates both the coagulation abnormalities seen after trauma by paracrine signalling on adjacent platelets at the site of developing thrombus as well as excessive inflammation through signalling to neutrophils and other inflammatory cells. We seek to address 3 key challenges related to this hypothesis. The first involves understanding the mechanisms by which HMGB1 promotes thrombosis through examining effects on key platelet adhesion molecules. The second examines the role of platelet HMGB1 in neutrophil activation and production of neutrophil extracellular traps (NETs) following trauma and the role of platelet-HMGB1 mediated NET production in acute lung injury. Finally, we propose the novel and innovative approach of using a TLR4 inhibitor that we have recently patented (US #9,072.760) and HMGB1 inhibitors packaged into a platelet-mimicking drug delivery nanovector for specific targeting of activated platelets at the site of inflammation and developing thrombus.