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Project 2: Metabolic regulation of host response and repair mechanisms to influenza A viral pneumonia

项目2：甲型流感病毒性肺炎宿主反应及修复机制的代谢调节

基本信息

批准号：
10696964
负责人：
NAVDEEP S CHANDEL
金额：
$ 49.37万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696964
关键词：
Acute Acute Respiratory Distress Syndrome Alveolar Alveolar Macrophages Attenuated Blood capillaries Cause of Death Cessation of life Clinical Complex Data Dendritic Cells Disease model Effector Cell Electron Transport Electron Transport Complex III Enzymes Epithelium Exudate Failure Floods Functional disorder Funding Opportunities Generations Genetic Glucose Glycolysis Goals Hospitals IL18 gene Immune response Immune signaling Impaired wound healing Impairment Infection Inflammasome Inflammation Inflammatory Influenza Influenza A virus Instruction Interferon Type I Knockout Mice Laboratories Lung Lung infections Macrophage Membrane Messenger RNA Metabolic Metabolic Control Metabolic Pathway Mitochondria Morbidity - disease rate Mus Natural regeneration Organ Pathology Patients Plasma Process Production Proton Pump Pyruvate Reactive Oxygen Species Recovery Regulation Research Research Personnel Signal Transduction Site Sodium Lactate Specificity Syndrome Testing Time Tissues Viral Viral Load result Viral Pneumonia Virus Virus Diseases Work conditional knockout cytokine disability functional restoration improved in vivo influenza infection inhibitor lactate dehydrogenase A lung repair monocyte mortality pharmacologic prevent pyruvate carrier receptor recruit repaired response tool

项目摘要

Project summary Viral pneumonia is currently among the most common causes of death in the world. Viral pneumonia impairs tissue repair leading to both in-hospital death and prolonged hospital-acquired disability. Understanding and targeting mechanisms that impair tissue repair after viral pneumonia therefore offers promise to both improve survival and prevent multiple organ morbidity after hospital discharge. In this Project and PPG, we hypothesize that ongoing inflammation after the influenza A virus (IAV) is cleared precludes proper lung repair. The cytosolic NOD-like receptor protein-3 (NLRP3)-dependent inflammasome complex initiates production of mature forms of the inflammatory cytokines IL-1 and IL18, inducing recruitment of effector cells to the site of infection that are essential to clearance of the influenza A virus. In addition, inflammasome activation within the monocyte derived alveolar macrophages participates in the ongoing inflammation observed in patients after influenza A virus clearance. Mitochondria have been proposed to be key regulators of NRLP3 dependent inflammasome activation. Our preliminary data demonstrate that inhibition of mitochondrial complex I or III as well as administration of sodium lactate, which does not alter the pH, attenuates inflammasome activation. Furthermore, our preliminary data indicate that monocyte-derived alveolar macrophages upon influenza infection display an increase in mitochondrial pyruvate carrier (MPC) mRNA, which diminishes pyruvate conversion into lactate by lactate dehydrogenase A (LDHA). We will test whether inflammasome dependent inflammation post-viral clearance in mice requires mitochondrial complexes I and III as well as lactate production in monocyte-derived alveolar macrophages using conditional knockout mice. Collectively these hypotheses will be tested in three interrelated Specific Aims: (1) Is mitochondrial complex I generated ROS required for influenza A induced NLRP3-dependent inflammasome activation in monocyte-derived alveolar macrophages? (2) Is mitochondrial complex III produced ROS necessary for influenza A induced NLRP3-dependent inflammasome activation in monocyte-derived alveolar macrophages? (3) Does in vivo lactate production decrease NLRP3-dependent inflammasome activation following influenza A virus infection in monocyte-derived alveolar macrophages.

项目总结