Regulation of Protein C Pathways

蛋白 C 通路的调节

基本信息

批准号：
10454075
负责人：
JOHN H GRIFFIN
金额：
$ 86.6万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454075
关键词：
2019-nCoV Abbreviations Acids Acute Address Affect Age Alteplase Animals Anticoagulants Biological Biological Products Blocking Antibodies Blood Coagulation Disorders Blood coagulation COVID-19 COVID-19 complications COVID-19 treatment Carboxypeptidase U Cardiovascular Diseases Cells Cessation of life Chronic Clinic Coagulation Process Collection Data Databases Defense Mechanisms Development Diabetes Mellitus Disease Endothelium Engineering Equilibrium F2R gene Factor V Factor X Feedback Fibrinolysis Future Generations Heart Injuries Homeostasis Host Defense Hyperactivity Hypertension ITGAM gene ITGB2 gene Immune Immune Cell Suppression In Vitro Inflammation Inflammatory Injury Injury to Kidney Integrins Islets of Langerhans Transplantation Kidney Transplantation Knowledge Laceration Lead Libraries Life Liver Lung infections Macrophage-1 Antigen Mediating Modeling Molecular Mus Nervous System Trauma Organ Outcome PAR-1 Receptor Pathology Pathway interactions Peptide Hydrolases Pharmacology Plasma Plasminogen Activator Inhibitor 1 Play Process Protein C Protein C Inhibitor Protein S Proteinase-Activated Receptors Pseudomonas Reaction Reagent Recombinants Regulation Reperfusion Injury Role SARS-CoV-2 infection Savings Sepsis Serine Protease Shock Signal Transduction Specificity Stroke Symptoms System Testing Therapeutic Thrombomodulin Thrombophilia Tissues Translating Translations Trauma Variant Whole-Body Irradiation activated Protein C activated protein C receptor base cell injury cell type citrate carrier clinical development comorbidity enzyme activity gastrointestinal graft vs host disease immunothrombosis improved in vivo insight ischemic injury lung injury man mortality mutant novel pre-clinical preclinical study protein protein interaction receptor severe COVID-19 success targeted treatment thromboinflammation tool trauma induced coagulopathy

项目摘要

Project Summary/Abstract Activated protein C (APC) is a naturally occurring plasma serine protease that has been translated to the clinic as a recombinant wild type or mutant biologic. In a diverse collection of preclinical animal injury models, pharmacologic APC’s provides many benefits. APC and the protein C systems contribute to the regulation of thromboinflammation that is critical for host defense, including defense versus SARS-CoV-2 infection. APC can act on diverse cell types, including immune cells for suppression of graft-versus-host disease. APC not only has anticoagulant activity but also initiates cell signaling via multiple receptors, in particular, via several protease activated receptors (PAR). APC-initiated cell signaling contributes to tissue homeostasis and host defense systems. Beneficial APC-initiated biased signaling is caused by specific cleavages of PAR1 and PAR3, and for some critical biologic activities, e.g., reducing mortality in sepsis, APC requires the integrin, Mac-1. Despite recent insights, there is a major gap in knowledge about protein-protein interactions between APC and its cellular receptors. Aim 1 studies will use a very extensive library of > five dozen recombinant APC mutants to provide a database regarding APC’s receptor specificities which will then enable engineering of APC mutants with receptor-specific selectivity, e.g., an APC mutant with highly selective PAR1-specific or PAR3-specific signaling capabilities or selectively specific for the I-domain of Mac-1. Such receptor-selective APC mutants will be useful reagents for deciphering which receptors play critical roles on cells in vitro or in animals in vivo, and they may lead to translation for novel APC mutants. To address the major problem of COVID-19, Aim 2 studies will characterize how murine COVID-19-like symptoms in SARS-CoV-2 infected hACE2 mice are influenced by endogenous protein C systems, e.g., by anticoagulant systems, by cytoprotective systems including anti- inflammation, anti-apoptosis, and endothelial barrier stabilization, and by fibrinolysis systems. Studies will define how these systems are modulated to be either hyperactive or hypoactive. This will provide new insights into how the protein C systems may be intertwined with defense versus SARS-CoV-2. The most promising cytoprotective- selective APC mutant (3K3A-APC) will be tested for COVID-19 therapy to advance potential translation. Aim 3 will characterize the multifaceted roles of APC in the pathobiology of acute traumatic coagulopathy. Studies will assess mechanisms by which disproportional APC generation contributes either to the development of acute traumatic coagulopathy involving Factor V inactivation and hyperfibrinolysis or, conversely, to protection of the integrity of organ function during and after acute traumatic coagulopathy by way of APC’s cytoprotective activities. The proposed studies will provide novel mechanistic insights and new APC variants which may aid translations to the clinic related to the APC pathways.

项目概要/摘要活化蛋白C (APC) 是一种天然存在的血浆丝氨酸蛋白酶，已转化为临床作为重组野生型或突变生物学，在多种临床前动物损伤模型中，药理学 APC 具有许多益处 APC 和蛋白 C 系统有助于调节。对宿主防御至关重要的血栓炎症，包括防御 SARS-CoV-2 感染。作用于多种细胞类型，包括抑制移植物抗宿主病的免疫细胞。抗凝血活性，但也通过多种受体启动细胞信号传导，特别是通过几种蛋白酶激活受体 (PAR) 启动的细胞信号传导有助于组织稳态和宿主防御。有益的 APC 启动的偏向信号传导是由 PAR1 和 PAR3 的特定裂解引起的。尽管 APC 需要整合素 Mac-1 来发挥某些关键的生物活性，例如降低脓毒症死亡率。最近的见解表明，关于 APC 及其细胞之间的蛋白质-蛋白质相互作用的知识存在重大差距目标 1 研究将使用超过五打重组 APC 突变体的非常广泛的文库来提供关于 APC 受体特异性的数据库，这将使 APC 突变体的工程化成为可能受体特异性选择性，例如具有高度选择性 PAR1 特异性或 PAR3 特异性信号传导的 APC 突变体此类受体选择性 APC 突变体将是有用的。用于破译哪些受体在体外细胞或动物体内发挥关键作用的试剂，它们可能为了解决 COVID-19 的主要问题，Aim 2 研究将导致新型 APC 突变体的翻译。描述 SARS-CoV-2 感染的 hACE2 小鼠中的鼠类 COVID-19 样症状如何受到影响内源性蛋白 C 系统，例如，通过抗凝系统、通过细胞保护系统，包括抗- 炎症、抗细胞凋亡和内皮屏障稳定，以及纤维蛋白溶解系统的研究将定义。如何将这些系统调节为过度活跃或低活跃这将为如何调节这些系统提供新的见解。蛋白 C 系统可能与对抗 SARS-CoV-2 的防御交织在一起，是最有前途的细胞保护作用。选择性 APC 突变体 (3K3A-APC) 将针对 COVID-19 疗法进行测试，以推进潜在的转化。将描述 APC 在急性创伤性凝血病病理学中的多方面作用。评估不成比例的 APC 生成导致急性发作的机制涉及因子 V 失活和纤溶亢进的创伤性凝血病，或者相反，保护凝血因子通过 APC 的细胞保护作用，在急性创伤性凝血病期间和之后维持器官功能的完整性拟议的研究将提供新颖的机制见解和新的 APC 变体，这可能会有所帮助。与 APC 途径相关的临床翻译。