Role of Secretoglobin 1A1 Protein in COVID-19-induced Thrombosis

分泌球蛋白 1A1 蛋白在 COVID-19 诱导的血栓形成中的作用

基本信息

批准号：
10255855
负责人：
APRILE L PILON
金额：
$ 25.65万
依托单位：
APCBIO INNOVATIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255855
关键词：
Acute Adhesions Adult Respiratory Distress Syndrome Aerosols American Animal Model Asthma Biological Biological Assay Blood Blood Coagulation Disorders Blood Platelets Blood Vessels Blood capillaries COVID-19 COVID-19 patient Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Chemosensitization Chronic Obstructive Airway Disease Coagulation Process Complication Coronavirus Development Disseminated Intravascular Coagulation Dyspnea Endothelium Equilibrium Exposure to Factor XIIIa Family Future Health Heart Diseases Homeostasis Hospitalization Human Hypertension Hypoxia Immune mediated destruction Immune response In Vitro Individual Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-6 Investigation Knowledge Lead Life Lung Measures Mediating Modeling Modification Nitrogen Oryctolagus cuniculus Oxygen Patients Phase Plasma Platelet aggregation Play Protein Isoforms Proteins Pulmonary Embolism Pulmonary Fibrosis Pulmonary Surfactants Rattus Reaction Reactive Nitrogen Species Reactive Oxygen Species Regulation Reporting Research Respiratory Insufficiency Role SARS-CoV-2 infection Small Business Innovation Research Grant Stroke Survivors TNF gene Therapeutic Thrombosis Transglutaminases Uteroglobin Vaccines Vascular Endothelial Cell Vascular Permeabilities Veterans Viral Respiratory Tract Infection Virus Virus Diseases aged airway epithelium alveolar epithelium cell injury cytokine disability ferric chloride immunoregulation improved in vitro activity in vivo in vivo Model indexing inflammatory marker innovation military service novel therapeutic intervention prevent repaired respiratory virus response service member severe COVID-19

项目摘要

Severe COVID-19 infection causes coagulopathies leading to stroke, pulmonary embolism, DVT, and disseminated intravascular coagulation (DIC). These complications of COVID-19 infection are often lethal and can lead to permanent disability in survivors. COVID-19-induced coagulopathy is atypical of most respiratory viral infections and it is important to understand the basis for these effects. Secretoglobin 1A1 (SCGB1A1, also known as CC10, CC16, CCSP, and uteroglobin) is a small globular immunomodulatory protein that is highly expressed in normal lungs by Club cells. Club cells are injured during COVID-19 infection, by the extreme inflammatory response and/or by direct viral infection. Club cell depletion results in SCGB1A1 deficiency. SCGB1A1 is important not only in maintaining lung homeostasis, function, and repair, but also circulates in the blood where it likely has additional homeostatic functions. SCGB1A1 is known to inhibit platelet aggregation and Factor XIIIa transglutaminase activity in vitro and may therefore play a role in vascular and/or blood homeostasis particularly as relates to balancing coagulation responses. SCGB1A1 is also known to be chemically modified by exposure to reactive oxygen and nitrogen species (ROS/RNS) during severe inflammatory responses in the lungs and the impact of these modifications on the anti-thrombotic activities of SCGB1A1 merits investigation. The proposed research will investigate the effects of ROS/RNS modification of SCGB1A1 on coagulation and clot formation in vitro, as well as in an animal model, and then will evaluate the potential depletion of SCGB1A1 and ROS/RNS-mediated modifications of native SCGB1A1 in COVID-19 patients and the potentiation of thrombosis in COVID-19 patients.

严重的Covid-19感染引起凝结剂，导致中风，肺栓塞，DVT，并传播血管内凝血（DIC）。这些并发症19 Covid-19感染通常是致命的，可能导致幸存者的永久残疾。 COVID-19引起的凝血病是大多数呼吸道病毒感染的非典型性，重要的是要了解这些影响的基础。 Secretoglobin 1A1（SCGB1A1，也称为CC10，CC16，CCSP和子宫球蛋白）是一种小球状免疫调节蛋白，在正常情况下高度表达俱乐部细胞肺。俱乐部细胞在19日感染期间受伤，通过极端炎症反应和/或通过直接病毒感染。俱乐部细胞耗竭会导致SCGB1A1 不足。 SCGB1A1不仅在维持肺稳态，功能和维修方面很重要，而且很重要而且还可以在血液中循环，那里可能具有额外的稳态功能。 SCGB1A1是已知可以在体外抑制血小板聚集和第十二个转谷氨酰胺酶活性因此，在血管和/或血液稳态中发挥作用，特别是与平衡有关凝血反应。还已知SCGB1A1通过暴露于化学修饰在严重的炎症反应中，活性氧和氮种（ROS/RN）在严重的炎症反应中肺和这些修饰对SCGB1A1抗栓性活动的影响调查。拟议的研究将研究ROS/RNS修饰的影响 SCGB1A1在体外以及动物模型中进行凝结和凝块形成，然后将评估SCGB1A1和ROS/RNS介导的天然修饰的潜在耗竭 CoVID-19患者的SCGB1A1和COVID-19患者的血栓形成增强。