ICAM-1 targeted thrombomodulin: an experimental therapeutic for the Acute Respiratory Distress Syndrome

项目摘要/摘要 急性呼吸窘迫综合征(ARDS)是影响20万人的主要健康问题 每年有患者死亡，约40%的受影响患者死亡。目前，还没有任何药理药物可以 改善结果。患者通常在急诊过程中相对较早出现在急诊室 病情，提示如果及时使用SAFE，肺损伤可能会被预防甚至逆转 和有效的治疗方法。作为一名执业急诊医生，这段临床经历激励着我 将我的职业生涯奉献给早期诊断生物技术的开发和转化， ARDS的预测和治疗。目前的项目涉及一种新的治疗方法，即 在小鼠肺损伤模型中提供保护，并提出三个具体目标来进一步定义其 作用机制，促进其临床前发展。 在ARDS中，血栓调节蛋白(TM)在细胞表面的表达减少 肺内皮细胞。这种蛋白通常与内皮蛋白受体(EPCR)配对 激活蛋白C，进而有助于减轻炎症，减少血浆蛋白泄漏，防止 微血管血栓形成。提案中描述的治疗方法增强了这种自然保护 与血管内皮细胞黏附分子ICAM-1结合的机制 炎症，并将重组TM锚定在细胞表面。以前的工作表明，这一点 方法使靶向治疗与自然表达的EPCR合作，促进蛋白C 在ARDS小鼠模型中预防性使用时，可激活并降低肺损伤的严重程度。 在第一个具体目标中，提出了一系列的体外微流控实验：1.模拟 在流动的人体血液和激活的肺内皮细胞界面上发生的复杂相互作用， 2.阐明以icam为靶点的TM如何减少凝血、免疫细胞黏附和血管。 这些模型中的屏障功能障碍。在第二个目标中，第二代化合物的合成和测试 提出了ICAM靶向疗法，并假设新配方将有所改善 药代动力学和延长肺的功能活性。在第三个目标中，广泛测试ICAM- 靶向TM在两种不同的ARDS小鼠模型中被提出，以确定疗效、剂量、治疗 时间窗口、安全性和作用机制。

Project Summary/Abstract The Acute Respiratory Distress Syndrome (ARDS) is a major health concern that affects 200,000 patients a year and kills ~40% of the patients affected. Currently, there are no pharmacologic agents that improve outcome. Patients often present to the Emergency Room relatively early in the course of the illness, suggesting that lung injury might be prevented or even reversed, given timely administration of safe and effective therapeutics. As a practicing Emergency Physician, this clinical experience has motivated me to dedicate my career to the development and translation of biotechnology for the early diagnosis, prognostication, and treatment of ARDS. The current project involves a novel therapeutic approach, which provides protection in a mouse model of lung injury, and proposes three specific aims to further define its mechanism of action and advance its pre-clinical development. In ARDS, there is a reduction in the amount of Thrombomodulin (TM) expressed on the surface of pulmonary endothelial cells. This proteins normally partners with the Endothelial Protein Receptor (EPCR) to activate protein C, which in turn helps to mitigate inflammation, reduce plasma protein leak, and prevent microvessel thrombosis. The therapeutics described in the proposal augment this natural protective mechanism by binding to ICAM-1, an endothelial cell adhesion molecule upregulated in the setting of inflammation, and anchoring recombinant TM to the cell surface. Previous work demonstrates that this approach enables partnering of the targeted therapeutic with naturally expressed EPCR, boosting protein C activation and reducing the severity of lung injury when used prophylactically in a mouse model of ARDS. In the first specific aim, a series of in vitro microfluidic experiments are proposed to: 1. model the complex interactions which occur at the interface of flowing human blood and activated lung endothelium, and 2. clarify how ICAM-targeted TM works to reduce coagulation, immune cell adhesion, and vascular barrier dysfunction in these models. In the second aim, the synthesis and testing of a second generation of ICAM-targeted therapeutics is proposed, with the hypothesis that the new formulation will improve pharmacokinetics and prolong functional activity in the lung. In the third aim, extensive testing of ICAM- targeted TM is proposed in two distinct murine models of ARDS, to determine efficacy, dosing, therapeutic time window, safety, and mechanism of action.