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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.

项目总结/摘要甲型流感病毒（IAV）流行与高发病率和死亡率相关。等并发症继发性细菌性肺炎和细胞因子风暴的发展导致多器官衰竭增加发病率和死亡率。尽管每年都有针对新出现的IAV毒株的疫苗开发，但并非所有受试者都能获得疫苗。接种疫苗或能够对疫苗产生强有力的保护性免疫应答。抗病毒药物，如奥司他韦在预防与严重IAV感染相关的死亡率方面并不完全有效。由此可见，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，药物，以限制与IAV感染相关的高全球医疗负担。TIMP-1（TIMP-1组织抑制剂）金属蛋白酶1）控制基质金属蛋白酶（MMP）的酶活性，并且是众所周知的调节细胞外基质（ECM）周转，但其对IAV疾病发病机制的贡献，没有被深入探索。我们的新的初步数据表明，血浆TIMP-1水平显著高于正常对照组。在诊断为大流行性H1N1和季节性IAV感染的患者中上调，并且水平与与PaO 2/FiO 2比值成反比。此外，我们使用免疫荧光染色的数据表明，TIMP- 1在脂肪成纤维细胞中显著诱导。与WT小鼠相比，Timp-1-/-小鼠具有减少的H1N1 IAV- 诱导的体重减轻;死亡率;肺损伤;适应性免疫应答和T细胞和B细胞增加激活和减弱的毛细渗漏。基于我们的数据，TIMP-1可能作为一个新的治疗靶点严重的IAV感染。本申请中提出的实验旨在1）识别调节， TIMP-1在IAV感染过程中的功能; 2）为TIMP-1在IAV感染过程中的作用机制提供了新的见解。缺乏在IAV感染期间提供更好的结果。这些研究的成功完成将为未来研究性新药（IND）的方式-使研究能够测试“同类第一”的安全性和有效性治疗靶向宿主反应，以降低与严重IAV相关的发病率和死亡率感染