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

• 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
• 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

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感染会导致凝血功能障碍，导致中风、肺栓塞、DVT， 和弥散性血管内凝血（DIC）。COVID-19感染的这些并发症 往往是致命的，并可能导致幸存者终身残疾。COVID-19诱导 凝血病是大多数呼吸道病毒感染的非典型性疾病， 这些影响的基础。分泌珠蛋白1A 1（SCGB 1A 1，也称为CC 10、CC 16、CCSP和CC 18）是一种免疫球蛋白。 子宫珠蛋白）是一种小的球状免疫调节蛋白，在正常子宫中高度表达。 俱乐部细胞的肺。在COVID-19感染期间，俱乐部细胞受到了极大的损伤， 炎症反应和/或直接病毒感染。俱乐部细胞耗竭导致SCGB 1A 1 缺陷SCGB 1A 1不仅在维持肺的稳态、功能和修复方面很重要， 而且还在血液中循环，在那里它可能具有额外的稳态功能。SCGB 1A 1是 已知在体外抑制血小板聚集和因子XIIIa转氨酶活性，并可 因此在血管和/或血液稳态中起作用 凝血反应还已知SCGB 1A 1通过暴露于 活性氧和氮（ROS/RNS）在严重炎症反应中的作用 肺以及这些修饰对SCGB 1A 1优点抗血栓活性的影响 调查该研究将探讨ROS/RNS修饰对细胞增殖的影响。 SCGB 1A 1在体外以及在动物模型中对凝血和凝块形成的影响，然后将 评估SCGB 1A 1的潜在消耗和ROS/RNS介导的天然细胞的修饰， COVID-19患者中的SCGB 1A 1和COVID-19患者中血栓形成的增强。