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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