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：
9886150
负责人：
Andreas Schwingshackl
金额：
$ 56.16万
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/9886150
关键词：
AGTR2 gene Acute Acute Lung Injury Affect Alveolar Animal Model Apoptosis Award Awareness Biochemical Markers Biological Assay Budgets Cell membrane Cells Clinical Clinical Research Co-Immunoprecipitations Complex Data Development Down-Regulation Drug Design Endothelial Cells Endothelium Environment Epithelial 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 Lung Inflammation Mass Spectrum Analysis Measures Mediating Membrane Potentials Molecular Target Morbidity - disease rate Morphology Mus Oxygen Oxygen Therapy Care Pathway interactions Patient-Focused Outcomes Patients Pharmacology Physiological Potassium Channel Process Respiratory Failure Role SECTM1 gene Savings Signal Pathway Signal Transduction Structure Supplementation Testing Therapeutic Translating alveolar epithelium biophysical properties cell type experimental study improved in vivo Model innovation lung injury mortality mouse model novel novel strategies overexpression oxygen toxicity patch clamp potassium channel protein TREK-1 prevent protective effect respiratory hypoxia 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.

项目摘要：意义：补充氧（高氧; HO）是最常应用的治疗住院的患者和急性缺氧呼吸衰竭（ARF）治疗的基石。众所周知，但是，HO暴露不仅可以促进现有的肺部损伤，还可以引起炎症和障碍其他健康肺部功能障碍。 HO引起的炎症反应特别损害了肺泡上皮和内皮细胞，导致细胞凋亡和肺泡屏障破坏。临床上，识别HO诱导的急性肺损伤（HALI）导致对氧毒性的认识提高努力最大程度地减少ARF患者的氧气暴露。尽管临床和实验研究已经确定哈利的潜在机制，目前尚无预防或抵消哈利的疗法，以及 ARF患者的住院时间一直保持不变二十年。这些发现强调迫切需要识别分子靶标，以促进针对HALI的合理药物设计。在寻找这种新目标时，我们发现了Trek-1钾通道是潜在的新钥匙哈利的监管机构。我们的初步数据支持了新的假设，即HO下皮和内皮TREK-1通道导致细胞膜去极化，随后打开电压 - 门控Ca2+通道，因此增加了炎症介质的分泌，细胞凋亡和肺泡屏障功能障碍。此外，我们建议提高跋涉1活动可以抵消这一点有害的级联。我们将以三个特定的目的检验这一假设：在AIM1中，我们将主要识别单元格类型（-s）受HO诱导的Trek-1下调的影响，使用上皮和内皮细胞特异性Trek-1 KO小鼠的影响与这些小鼠分离的模型和原代细胞。在AIM 2中，我们将确定Trek-1的保护作用使用新型TREK-1激活化合物，新的细胞类型特异性TREK-1，对HAI的增强从这些小鼠中分离出的过表达小鼠模型，以及原发性上皮细胞和内皮细胞。在目标3中我们将剖析上皮和内皮跋涉1的结构组成和生物物理特性在基线和HO条件下的通道，并提出了一种新的信号传导机制通道可以调节哈利期间的炎症和屏障功能障碍。这项研究将通过建立异常上皮和内皮跋涉 - 1在肺中作为先前未识别的途径在HALI中的信号传导，而Trek-1激活为第一个靶向针对哈利的治疗方法。