Regulation of Protein C Pathways

蛋白 C 通路的调节

• 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
• 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

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.

项目总结/摘要 活化蛋白C（APC）是一种天然存在的血浆丝氨酸蛋白酶，已被翻译到临床 作为重组野生型或突变生物制剂。在各种临床前动物损伤模型中， 药理学APC提供了许多益处。APC和蛋白C系统有助于调节 血栓炎症是宿主防御的关键，包括防御SARS-CoV-2感染。APC可以 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。APC不仅拥有 抗凝血活性，而且还通过多种受体，特别是通过几种蛋白酶启动细胞信号传导 活化受体（PAR）。APC启动的细胞信号转导有助于组织稳态和宿主防御 系统.有益的APC启动的偏置信号传导是由PAR 1和PAR 3的特异性裂解引起的， 一些关键的生物活性，例如，降低败血症的死亡率，APC需要整合素Mac-1。尽管 最近的见解，有一个主要的差距，在知识之间的蛋白质-蛋白质相互作用的APC和其细胞 受体。目的1研究将使用一个非常广泛的> 50打重组APC突变体库，以提供一个新的APC突变体库。 关于APC的受体特异性的数据库，其然后将使得能够工程化APC突变体， 受体特异性选择性，例如，具有高度选择性PAR 1特异性或PAR 3特异性信号传导的APC突变体 功能或选择性地特定于Mac-1的I域。这种受体选择性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起关键作用的试剂，它们可以 导致新APC突变体翻译。为了解决COVID-19的主要问题，目标2研究将 描述SARS-CoV-2感染hACE 2小鼠的COVID-19样症状如何受到以下因素的影响： 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、抗凋亡和内皮屏障稳定，以及纤维蛋白溶解系统。研究将定义 这些系统是如何被调节成过度活跃或功能减退的。这将提供新的见解， 蛋白C系统可能与抗SARS-CoV-2的防御交织在一起。最有希望的细胞保护- 选择性APC突变体（3 K3 A-APC）将用于COVID-19治疗，以促进潜在的翻译。目标3 将描述APC在急性创伤性凝血病病理生物学中的多方面作用。研究将 评估不成比例的APC生成促进急性胰腺炎发展的机制， 涉及因子V失活和纤维蛋白溶解亢进的创伤性凝血病，或相反， APC细胞保护作用对急性创伤性凝血病时、后器官功能完整性的影响 活动拟议的研究将提供新的机制见解和新的APC变体， 翻译到与APC途径相关的临床。