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

ICAM-1 靶向血栓调节蛋白：急性呼吸窘迫综合征的实验性治疗方法

基本信息

批准号：
9789930
负责人：
Colin Fred Greineder
金额：
$ 13.23万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789930
关键词：
Accident and Emergency department Adhesions Adult Respiratory Distress Syndrome Affect Animal Model Animals Anti-inflammatory Area Bacterial Pneumonia Binding Biodistribution Biotechnology Blood Blood Platelets Blood Vessels CD31 Antigens Cell Adhesion Cell Adhesion Molecules Cell Culture System Cell surface Cells Chimeric Proteins Clinical Clinical Trials Coagulation Process Complex Data Development Dose Drug Kinetics Early Diagnosis Emergency Care Emergency Department Physician Endothelial Cells Endothelium Engineering Exposure to Failure Formulation Functional disorder Generations Genetic Health Human Immune Immunoglobulin Fragments In Vitro Incidence Inflammation Injury Intensive Care Intercellular adhesion molecule 1 Intervention Investigational Therapies Kinetics Laboratories Leukocytes Life Lung Measures Mediating Medical Microfluidics Modeling Monoclonal Antibodies Mus Outcome Pathogenesis Pathogenicity Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacology Plasma Proteins Process Protein C Protein Engineering Proteins Recombinants Role Safety Sepsis Series Severities Signal Transduction Site Surface Techniques Testing Therapeutic Thrombin Thrombomodulin Thrombosis Time Toxic effect Translations Trauma Treatment Efficacy United States Whole Blood Work activated Protein C activated protein C receptor career cytokine experience experimental study human disease immune activation improved improved outcome in vivo intercellular cell adhesion molecule interest lung injury mortality mouse model novel novel therapeutic intervention preclinical development prevent prognostic prophylactic protective effect protein activation receptor residence targeted treatment therapeutic evaluation therapeutic target translation to humans

项目摘要

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.

项目摘要/摘要急性呼吸窘迫综合征（ARDS）是影响200,000的主要健康问题患者一年，杀死约40％的患者。目前，没有药理学剂改善结果。患者经常在急诊室相对较早出现在急诊室鉴于及时管理安全的疾病，表明可以预防甚至逆转肺损伤和有效的治疗学。作为一名执业急诊医师，这种临床经验激发了我的动力为了将我的职业致力于生物技术的发展和翻译以进行早期诊断，预后和ARDS的处理。当前的项目涉及一种新型的治疗方法，在肺部损伤的鼠标模型中提供保护，并提出了三个特定目的，以进一步定义其作用机理并推进其前临床前的发展。在ARDS中，在表面上表达的血小板调节蛋白（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）合作激活蛋白C，这又有助于减轻炎症，减少血浆蛋白泄漏并防止微血管血栓形成。提案中描述的治疗剂增强了这种自然保护性通过与ICAM-1结合的机理，ICAM-1是一种内皮细胞粘附分子，在地上上调炎症，并将重组TM锚定在细胞表面。以前的工作证明了这一点方法使靶向治疗与自然表达的EPCR合作，增强蛋白质C 当在ARDS小鼠模型中预防时，激活并降低了肺损伤的严重程度。在第一个特定目的中，提出了一系列体外微流体实验：1。建模在流动的人血和活化的肺内皮的界面上发生的复杂相互作用，和2。阐明靶向ICAM的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，第二代的合成和测试提出了靶向ICAM的治疗剂，假设新配方将改善肺中的药代动力学和延长功能活性。在第三个目标中，对ICAM的广泛测试在两个不同的ARDS模型中提出了靶向TM，以确定功效，剂量，治疗性时间窗口，安全性和作用机理。