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: 9484277
• 负责人: Matthew D Neal
• 金额: $ 36.57万
• 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/9484277
• 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：创伤是全世界年轻人死亡的主要原因，据估计 仅在美国，每年的医疗保健费用就高达 4000 亿美元。创伤幸存者遭受痛苦 器官衰竭和血栓栓塞并发症等严重发病率，这些并发症在很大程度上是由 部分原因是过度炎症和凝血异常的恶性级联反应。缺乏理解 创伤后调节炎症和凝血病的机制提出了一项重要的国际研究 健康问题，因为缺乏治疗目标严重限制了干预能力。像这样， 了解创伤、炎症和凝血病之间的联系是制定治疗策略的关键 帮助每年数百万创伤幸存者预防器官衰竭和发病。我们实验室最近 在理解潜在联系方面取得了巨大进步。我们已经确定了通过密钥发出的信号 先天免疫受体，血小板上的 Toll 样受体 4 (TLR4) 在一定程度上是造成过度 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 在现场，血小板既充当止血的初始反应者，又充当止血的早期关键效应细胞。 炎症的发生。尽管有这些发现，引发血小板“功能障碍”的配体 通过 TLR4 的作用尚不清楚。重要的是，已知严重的创伤可以通过以下方式激活先天免疫系统： 释放大量危险相关分子模式分子 (DAMP)。目前的建议 基于高迁移率组框 1 (HMGB1)、关键 DAMP 和充分表征的 TLR4 的假设 配体，在创伤后由血小板特异性释放并调节凝血异常 创伤后，通过在血栓形成部位的相邻血小板上的旁分泌信号传导来观察 通过向中性粒细胞和其他炎症细胞发出信号而导致过度炎症。我们寻求解决 3 与这一假设相关的主要挑战。第一个涉及了解 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。第二次检查 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 创伤后以及血小板-HMGB1 介导的 NET 产生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药物递送纳米载体，用于特定 将活化的血小板靶向炎症和形成血栓的部位。