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Targeting metabolic pathways in lung injury

针对肺损伤的代谢途径

基本信息

批准号：
10536749
负责人：
Kevin Shenderov
金额：
$ 7.93万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2022-09-15 至 2023-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536749
关键词：
Acute Lung Injury Acute Respiratory Distress Syndrome Affect Albumins Animal Model Anti-Inflammatory Agents Antioxidants Basic Science Biology Bronchoalveolar Lavage Fluid COVID-19 patient COVID-19 pneumonia COVID-19/ARDS Cell Count Cell surface Cells Clinical Trials Critical Illness Cysteine Data Data Set Development Disease Drops Endothelial Cells Epithelial Epithelial Cells Equilibrium Exhibits Functional disorder Funding Glutathione Glutathione Metabolism Pathway Harvest Human Immune Individual Inflammation Inflammatory Inflammatory Response Inhalation Injury Inositol Laboratory Research Lead Life Liquid substance Lung Lymphocyte Mass Spectrum Analysis Measurement Measures Metabolic Metabolic Pathway Metabolism Modeling Multiple Organ Failure Mus Oxidation-Reduction Oxidative Stress Oxidative Stress Pathway PARP9 gene PTPRC gene Patients Peptides Pharmacology Physicians Play Pneumococcal Infections Pneumococcal Pneumonia Pneumonia Population Reduced Glutathione Resolution Role Sampling Scientist Sepsis Stimulus Streptococcus pneumoniae Supplementation Syndrome Testing Time Tissue Sample Work base cell type cytokine experimental study falls immune activation immune function improved in vivo insight lens lung histology lung injury macrophage magnetic beads metabolic profile metabolomics mortality mouse model neutrophil novel novel strategies novel therapeutic intervention novel therapeutics oxidative damage pneumonia model skills sugar therapeutic target ventilation wound healing

项目摘要

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) affects over 200,000 individuals in the US and over 3 million worldwide each year. This highly lethal syndrome can occur due to various types of lung injury (for example pneumonia, inhalational injury, or sepsis). Thirty to forty percent of patients with this condition will die – usually of multiorgan failure. There are no available pharmacologic therapies for ARDS and treatment is essentially supportive. Novel therapies for this condition are therefore urgently needed. Studies of ARDS pathophysiology have shown that lung injury is highly inflammatory, but numerous different anti-inflammatory therapies that have been tested in clinical trials have failed to reduce mortality from this disease. A potential novel approach to treating ARDS may be found in the nascent field of immunometabolism, which has shown that activation of immune cells (such as the lung macrophages and neutrophils that are known to play an important role in ARDS) leads to major metabolic changes that are necessary to support pro-inflammatory responses. Understanding the metabolic pathways that support detrimental inflammation during acute lung injury could lead to treatments for ARDS that hasten resolution of inflammation and promote wound healing through modulation of metabolism. In this proposal, metabolic pathways that are altered during lung injury will be studied in animal models as well as in human biospecimens. Our preliminary data has shown that two particular metabolites–myo-inositol and glutathione—rapidly drop in abundance in three different animals models of acute lung injury. Moreover, treating mice with myo-inositol or glutathione in one of our models—pneumonia due to Streptococcus pneumoniae, also known as “pneumococcus”—significantly improved their survival. Myo-inositol and glutathione can both act as antioxidants, so we hypothesize that they are depleted during lung injury because of oxidative stress. Supplementation with these metabolites may improve survival during pneumococcal infection by reducing oxidative injury. In Aim 1 of this project, the cellular basis of the changes in myo-inositol and glutathione metabolism will be examined by separating immune cells and non-immune cells (e.g. endothelial and epithelial cells) from the lungs of mice with pneumococcal pneumonia and measuring metabolite abundance in these separated cell populations. In Aim 2, we will examine whether treatment of mice with myo-inositol or glutathione reduces levels of oxidative stress in the pneumococcal pneumonia model and whether this correlates with reduced inflammation and lung injury. In Aim 3, we will measure levels of metabolites in de-identified bronchoalveolar lavage fluid samples from patients with ARDS due to COVID-19 pneumonia compared to healthy controls to determine whether myo-inositol and glutathione levels fall during human ARDS as they do in our mouse models. Completing this project will provide fundamental insights into the biology of ARDS and could potentially lead to novel therapies for this deadly disease. It will also provide the applicant with an opportunity to develop skills needed to become a successful physician-scientist.

项目总结