Trek-1 Potassium Channels Protect from Hyperoxia-induced Acute Lung Injury

Trek-1 钾通道可预防高氧引起的急性肺损伤

基本信息

批准号：
10586093
负责人：
Andreas Schwingshackl
金额：
$ 55.07万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586093
关键词：
AGTR2 gene Acute Lung Injury Affect Alveolar Animal Model Apoptosis Award Awareness Biochemical Markers Biological Assay Budgets Cell Separation Cell membrane Cells Clinical Clinical Research Co-Immunoprecipitations Complex Data Development Down-Regulation Drug Design Endothelial Cells Endothelium Environment Epithelial Cells Epithelium Exposure to Fluorometry Functional disorder Genetic Enhancement Healthcare Histologic Hospitalization Human Hyperoxia In Vitro Individual Inflammation Inflammation Mediators Inflammatory Response Intervention Knockout Mice Label Length Life Lung Mass Spectrum Analysis Measures Mediating Membrane Potentials Mentored Clinical Scientist Development Program Molecular Target Morbidity - disease rate Morphology Mus Oxygen Oxygen Therapy Care Pathway interactions Patient-Focused Outcomes Patients Physiological Potassium Channel Process Pulmonary Inflammation Role Signal Pathway Signal Transduction Structure Supplementation Testing Therapeutic Translating acute hypoxemic respiratory failure alveolar epithelium biophysical properties cell type experimental study hyperoxia induced lung injury improved in vivo Model innovation lung injury mortality mouse model novel novel strategies overexpression oxygen toxicity patch clamp pharmacologic potassium channel protein TREK-1 prevent protective effect targeted treatment voltage

项目摘要

PROJECT SUMMARY: Significance: Oxygen supplementation (hyperoxia; HO) is the most frequently applied therapy for hospitalized patients and the cornerstone of treatment for acute hypoxic respiratory failure (ARF). It is well known, however, that HO exposure can not only promote existing lung injury but also initiate inflammation and barrier dysfunction in otherwise healthy lungs. The inflammatory response evoked by HO is particularly damaging to alveolar epithelial and endothelial cells causing cellular apoptosis and alveolar barrier disruption. Clinically, the recognition of HO-induced acute lung injury (HALI) led to an increased awareness of oxygen toxicity and efforts to minimize oxygen exposure for ARF patients. Although clinical and experimental studies have identified several potential mechanisms underlying HALI, currently no therapies exist to prevent or counteract HALI, and the length of hospitalization of ARF patients has remained unchanged for two decades. These findings underscore the urgent need for identifying molecular targets to facilitate rational drug design against HALI. In the search for such new targets, we discovered TREK-1 potassium channels as potential new key regulators of HALI. Our preliminary data support the novel hypothesis that HO downregulates epithelial and endothelial TREK-1 channels, which results in cell membrane depolarization, subsequent opening of voltage- gated Ca2+ channels, and as a consequence increased inflammatory mediator secretion, cell apoptosis and alveolar barrier dysfunction. Furthermore, we propose that enhancement of TREK-1 activity can counteract this injurious cascade. We will test this hypothesis in three Specific Aims: In Aim1 we will identify the cell type(-s) predominantly affected by HO-induced TREK-1 downregulation, using epithelial and endothelial cell-specific TREK-1 KO mouse models and primary cells isolated from these mice. In Aim 2 we will determine the protective effects of TREK-1 enhancement against HALI using novel TREK-1 activating compounds, new cell type-specific TREK-1 overexpressing mouse models, and primary epithelial and endothelial cells isolated from these mice. In Aim 3 we will dissect the structural composition and biophysical properties of epithelial and endothelial TREK-1 channels at baseline and under HO conditions, and propose a novel signaling mechanism by which TREK-1 channels could regulate inflammation and barrier dysfunction during HALI. This study will impact the field of acute lung injury by establishing aberrant epithelial and endothelial TREK- 1 signaling in the lung as a previously unrecognized pathway in HALI, and TREK-1 activation as the first targeted therapeutic approach against HALI.