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

项目总结/摘要 急性呼吸窘迫综合征（ARDS）是一个主要的健康问题，影响20万 患者，并杀死约40%的患者。目前，还没有药物制剂， 改善结果。患者通常在治疗过程中相对较早地出现在急诊室。 疾病，提示肺损伤可以预防，甚至逆转，给予及时的安全 和有效的治疗方法。作为一名执业急诊医师，这一临床经验激励了我 致力于早期诊断生物技术的发展和转化， 急性呼吸窘迫综合征的治疗。目前的项目涉及一种新的治疗方法， 在小鼠肺损伤模型中提供了保护，并提出了三个具体目标，以进一步确定其 研究其作用机制，推进其临床前开发。 在急性呼吸窘迫综合征（ARDS）中，血小板表面表达的血栓调节蛋白（TM）的量减少， 肺内皮细胞这种蛋白质通常与内皮蛋白受体（EPCR）结合 激活蛋白C，这反过来有助于减轻炎症，减少血浆蛋白泄漏， 微血管血栓形成该提案中描述的治疗方法增强了这种天然的保护作用， ICAM-1是一种内皮细胞粘附分子，在血管内皮细胞凋亡的情况下上调。 炎症，并将重组TM锚定到细胞表面。以前的研究表明， 这种方法能够将靶向治疗与天然表达的EPCR结合起来， 当在ARDS的小鼠模型中治疗性地使用时，本发明的组合物具有显著的抗活化和降低肺损伤的严重性的作用。 在第一个具体目标中，提出了一系列体外微流控实验：1。模拟 在流动的人体血液和活化的肺内皮的界面处发生的复杂的相互作用， 和2.阐明ICAM靶向TM如何减少凝血、免疫细胞粘附和血管 这些模型中的屏障功能障碍。在第二个目标中，合成和测试第二代 ICAM-靶向治疗提出，假设新的配方将改善 药物代谢动力学和延长肺中的功能活性。在第三个目标中，广泛测试ICAM- 在两种不同的ARDS鼠模型中提出了靶向TM，以确定其功效、剂量、治疗性和耐受性。 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.