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Caspase-1, the Microvascular Endothelium, and Infection

Caspase-1、微血管内皮和感染

基本信息

批准号：
9043174
负责人：
JONATHON PETER AUDIA
金额：
$ 37.88万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043174
关键词：
Adult Respiratory Distress Syndrome Affect Anti-Inflammatory Agents Anti-inflammatory Biological Assay Biology CASP1 gene Case Study Cell Death Cell physiology Cells Cellular Stress Clinical Trials Cysteine Data Endothelial Cells Endothelium Enzymes Eukaryotic Cell Failure Fluorescence Generations Glycolysis Glycolysis Inhibition Goals Health Homologous Gene Human Immune Immunoblotting Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-18 Life Link Lung Measures Mediating Mitochondria Mitochondrial Proteins Modeling Molecular Mutagenesis Nitrogen Outcome Oxygen Pathogenesis Patient-Focused Outcomes Patients Pattern recognition receptor Peptide Hydrolases Phospholipase A2 Positioning Attribute Prevalence Process Pseudomonas aeruginosa Pulmonary Edema Recovery Reporter Resolution Respiration Rickettsia prowazekii Role Severities Signal Pathway Signal Transduction Site-Directed Mutagenesis Stem cells Stress Testing Toxin Ventilator Venus base biological adaptation to stress combat cytokine extracellular glycation inhibitor/antagonist interleukin-1beta-converting enzyme inhibitor macrophage monocyte mortality novel outcome prediction pathogen programs receptor research study respiratory response scaffold targeted treatment therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Despite compelling experimental evidence linking inflammation to the pathogenesis of Acute Respiratory Distress Syndrome (ARDS), anti-inflammatory clinical trials have systematically failed to demonstrate beneficial effects in patients. This failure is often ascribed to the interrelated prospects that pan-suppression of inflammation is deleterious or that anti-inflammatories also inhibit protective stress responses. Thus, identifying novel targets to treat ARDS requires an understanding of the basic biology underlying key molecules that drive both pro-inflammatory responses in immune cells and protective stress adaptation programs in non-immune cells. Preliminary Data show that, in addition to inducing pro-inflammatory responses in macrophages, Caspase-1 protease activation protects Pulmonary Microvascular Endothelial Cell (PMVEC) and Pulmonary Arterial Endothelial Cell (PAEC) barrier function in response to infection. Additional data presented herein support a model in which Caspase-1 degrades glycolytic and mitochondrial proteins in PMVECs and PAECs as a protective strategy that limits accumulation of advanced N-glycation end products (AGEs) and reactive oxygen/nitrogen species (RS) induced by infection. Intriguingly, the model opportunistic pathogen (Pseudomonas aeruginosa) and vasculotropic pathogen (Rickettsia prowazekii) used in these studies both deploy homologous secreted phospholipase A2 toxins (ExoU) that inhibit Caspase-1 activation. The proposed experiments will test the Hypothesis that Caspase-1 activation in PMVECs and PAECs elicits degradation of glycolytic and mitochondrial proteins as an adaptive stress response to protect barrier function. Specific Aim 1 will elucidate mechanisms of Caspase-1 activation in PMVECs and PAECs by: 1.1) Defining the mechanisms by which PMVECs and PAECs sense infection at the level of Inflammasome signaling using a Split Venus fluorescence complementation reporter. 1.2) Determining mechanisms by which the ExoU secreted toxin inhibits Caspase-1 activation using phospholipase A2 signaling inhibitors. Specific Aim 2 will elucidate mechanisms of Caspase-1-induced stress responses in PMVECs and PAECs by: 2.1) Elucidating glycolytic and mitochondrial proteins degraded by Caspase-1 and validating targets by site-directed mutagenesis and enzyme function assays. 2.2) Determining whether Caspase-1 protects PMVEC and PAEC barrier function during infection. Molecular and pharmacologic approaches will be used to either down-regulate or up-regulate Caspase-1 followed by assessment of barrier function, AGEs, and RS. Inhibitors of glycolytic intermediates, AGEs, and/or RS will unveil their roles in barrier demise. Specific Aim 3 will correlate Caspase- 1 activation and mitochondrial function with ARDS patient outcomes by: 3.1) Measuring active Caspase-1 and mitochondrial respiration in immune cells and non-immune cells. 3.2) Correlating outcomes with patient mortality and ventilator-free days. Long-term impact on human health and translational potential lie in identifying targets for therapies to treat ARDS, which are currently lacking.