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Mechanistic Insights of TIMP-1 in Influenza Virus Infection

TIMP-1 在流感病毒感染中的机制见解

基本信息

批准号：
10615782
负责人：
Xiaoyun Wang
金额：
$ 7.55万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615782
关键词：
18 year old Activated Lymphocyte Acute Lung Injury Antiviral Agents Apoptotic Attenuated B-Cell Activation B-Lymphocytes Bacterial Pneumonia Biological Response Modifiers Blood Vessels Blood capillaries Body Weight decreased Capillary Permeability Cell Proliferation Cells Cessation of life Data Development Diagnosis Extracellular Matrix Extracellular Matrix Degradation Future Goals Healthcare Hospitalization Immune response Immunofluorescence Immunologic Impairment In Vitro Individual Inflammatory Response Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Investigational Drugs Knowledge Link Lung Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mediating Morbidity - disease rate Multiple Organ Failure Mus Myofibroblast Oseltamivir Outcome Oxygen Pathogenesis Patients Peptide Hydrolases Plasma Proteins Pulmonary Inflammation Regulation Role Seasons Severities Stains Structure of parenchyma of lung T-Lymphocyte Testing Tissue Inhibitor of Metalloproteinase-1 Vaccinated Vaccinee Vaccines Viral Proteins Virus Virus Diseases Virus Replication Wild Type Mouse adaptive immune response care burden cell type cytokine release syndrome effective therapy epidemic virus experimental study flu global health human subject influenza infection insight lung injury mortality new therapeutic target novel pandemic disease prevent protective effect recruit safety testing seasonal influenza therapeutic target transdifferentiation vaccine development

项目摘要

PROJECT SUMMARY/ ABSTRACT Influenza A virus (IAV) epidemics are associated with high morbidity and mortality. Complications such as the development of secondary bacterial pneumonia and cytokine storm leading to multi-organ failure increase morbidity and mortality. Although vaccines are developed annually for emerging IAV strains, not all subjects are vaccinated or able to mount robust protective immune responses to the vaccines. Anti-viral drugs such as oseltamivir are not fully effective at preventing mortality associated with severe IAV infections. Thus, there is an urgent need to identify new therapeutic targets to facilitate the development of more effective antiviral agents to limit the high global healthcare burden associated with IAV infections. TIMP-1 (tissue inhibitor of metalloproteinases 1) controls the enzymatic activity of matrix metalloproteinases (MMPs) and is well-known for regulating extracellular matrix (ECM) turnover, but its contributions to the pathogenesis of IAV disease have not been deeply explored. Our novel preliminary data showed that plasma TIMP-1 levels are significantly upregulated in patients diagnosed with pandemic H1N1 and seasonal IAV infections, and levels correlate inversely with the PaO2/FiO2 ratio. Furthermore, our data using immunofluorescence staining suggested TIMP- 1 is dramatically induced in lipofibroblasts. Compared with WT mice, Timp-1-/- mice have reduced H1N1 IAV- induced body weight loss; mortality; lung injury; increased adaptive immune responses and T cell and B cell activation, and attenuated capillary leak. Based on our data, TIMP-1 might serve as a novel therapeutic target during serious IAV infection. The experiments proposed in this application aim to 1) identify the regulation and function of TIMP-1 during the IAV infection; 2) provide novel insights into the mechanism by which Timp-1 deficiency provides better outcomes during IAV infection. Successful completion of these studies will pave the way for future investigational new drug (IND)-enabling studies to test the safety and efficacy of a “first in class” therapeutic targeting the host response to reduce the morbidity and mortality associated with serious IAV infection.

项目摘要/摘要甲型流感病毒(IAV)流行与高发病率和高死亡率有关。并发症，如继发性细菌性肺炎和细胞因子风暴导致多器官衰竭增加发病率和死亡率。尽管针对新出现的IAV毒株每年都会开发疫苗，但并非所有受试者接种疫苗或能够对疫苗产生强大的保护性免疫反应。抗病毒药物，如奥司他韦在预防与严重IAV感染相关的死亡方面并不完全有效。因此，有迫切需要确定新的治疗靶点，以促进更有效的抗病毒药物的开发限制与IAV感染相关的高全球医疗负担的药物。TIMP-1(组织抑制因子金属蛋白酶1)控制基质金属蛋白酶(MMPs)的酶活性，众所周知用于调节细胞外基质(ECM)的代谢，但其在IAV疾病发病机制中的贡献没有得到深入的探索。我们新的初步数据显示，血浆TIMP-1水平显著在确诊为甲型H1N1大流行性流感和季节性IAV感染的患者中上调，并且水平与与PaO2/FiO2比值成反比。此外，我们的免疫荧光染色数据表明TIMP- 1在脂成纤维细胞中被显著诱导。与WT小鼠相比，TIMP-1-/-小鼠减少了H1N1禽流感病毒- 诱导体重减轻；死亡率；肺损伤；获得性免疫反应增强以及T细胞和B细胞活化，减少毛细管渗漏。根据我们的数据，TIMP-1可能成为一种新的治疗靶点在严重的IAV感染期间。本申请中提出的实验旨在1)识别规则和 TIMP-1在IAV感染中的作用；2)为TIMP-1的作用机制提供了新的见解在IAV感染期间，缺乏可以提供更好的结果。这些研究的成功完成将为未来研究新药(IND)的途径--使研究能够测试“一流”药物的安全性和有效性针对宿主反应的治疗，以降低与严重IAV相关的发病率和死亡率感染。