Mechanistic Elucidation and Targeted Therapy of Platelet Dysfunction After Trauma

创伤后血小板功能障碍的机制阐明和靶向治疗

• 批准号: 9336940
• 负责人: Matthew D Neal
• 金额: $ 35.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336940
• 关键词: Acute Lung Injury; Address; Blood Coagulation Disorders; Blood Platelets; Blood coagulation; Cause of Death; Cell Adhesion Molecules; Cells; Cessation of life; Coagulation Process; Disease; Drug Delivery Systems; Effector Cell; Functional disorder; HMGB1 Protein; Health Care Costs; Hemorrhage; Hemostatic function; Immunologic Receptors; Inflammation; Inflammatory; Innate Immune System; International Health Problems; Legal patent; Ligands; Link; Mediating; Molecular; Morbidity - disease rate; Mus; Nanotechnology; Neutrophil Activation; Organ failure; Paracrine Communication; Pattern; Production; Role; Signal Transduction; Site; Survivors; TLR4 gene; Thrombosis; Thrombus; Trauma; Traumatic injury; United States; base; extracellular; inhibitor/antagonist; innovation; nanovector; neutrophil; novel; novel therapeutics; prevent; targeted treatment; therapeutic target; treatment strategy

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.

项目摘要：创伤是全球年轻人的主要死亡原因，估计 仅在美国，每年的医疗保健费用为每年4000亿美元。创伤的幸存者受苦 从处于器官衰竭和血栓栓塞并发症的形式的严重发病率，这些并发症驱动很大 部分，由于过度炎症和恶性凝血异常。缺乏理解 创伤后的调节炎症和凝结病的机制提出了一个主要的国际 健康问题，因为缺乏治疗目标严重限制了干预的能力。像这样， 了解创伤，炎症和凝血病之间的联系是制定策略的关键 有助于预防数百万年度创伤幸存者的器官衰竭和发病率。我们的实验室最近有 迈向理解潜在联系的大步向前。我们已经确定通过钥匙发出信号 先天免疫受体，平台上的类似收费受体4（TLR4），部分原因是两者都过多 小鼠严重出血后的炎症和凝血病。这些发现是早期进步的关键 在现场，由于血小板是止血中的初始反应者，但也是早期的关键效应细胞 炎症的启动。尽管有这些发现，但触发这种血小板的“功能障碍”的配体 通过TLR4是未知的。重要的是，已知严重的创伤可以通过 释放大量危险相关的分子模式分子（潮湿）。目前的提议 基于以下假设：高搬运组框1（HMGB1），一个键湿且表征良好的TLR4 配体是由创伤后的血小板专门释放的，并调节了这两种异常 通过旁分泌信号传导在发育中的相邻血小板上的旁分泌信号转导后观察到 通过信号向中性粒细胞和其他炎症细胞信号传导过度炎症。我们寻求解决3 与该假设有关的主要挑战。首先涉及了解HMGB1的机制 通过检查对关键血小板粘附分子的影响促进血栓形成。第二个检查 血小板HMGB1在中性粒细胞激活和中性粒细胞外陷阱（NET）中的作用 在创伤和血小板-HMGB1介导的急性肺损伤中的净产生作用之后。最后，我们 提出了我们最近已获得专利的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药物输送纳米伏源 靶向激活的血小板在炎症部位并发展为血栓。