Role of hypercapnia on the lung airways

高碳酸血症对肺气道的作用

基本信息

批准号：
10115793
负责人：
Jacob I Sznajder
金额：
$ 46.01万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115793
关键词：
Acidosis Actins Acute Affect Applications Grants Bacterial Infections Blood Bronchopulmonary Dysplasia CASP7 gene CSPG4 gene Calcineurin Calpain Carbon Dioxide Carotid Body Cell physiology Cells Chronic Chronic Obstructive Airway Disease Chronic lung disease Clinical Cytoskeleton Data Deposition Disease Down-Regulation DsRed Exposure to Extracellular Matrix G Actin Gases Glomus Cell Guidelines Health Human Hypercapnia Hypoxia Immune response Impairment In Vitro Individual Intensive Care Units Knockout Mice Lead Lung Lung diseases Morbidity - disease rate Mus Muscle Muscle Contraction Muscle function Nitric Oxide Outcome Oxygen PPP3CA gene Partial Pressure Pathway interactions Patients Preparation Reporting Research Research Personnel Role Serum Signal Pathway Slice Smooth Muscle Myocytes Testing Tissues Transgenic Organisms United States Validation Virus Diseases adverse outcome airway hyperresponsiveness airway remodeling alveolar epithelium body sense cofilin connective tissue growth factor design experimental study in vivo insight knock-down mortality novel novel therapeutics paxillin polymerization prevent respiratory smooth muscle transcriptome

项目摘要

Project Summary Oxygen and nitric oxide activate cellular signaling pathways, which are important in lung health and diseases. However, much less is known about the mechanisms by which lung cells (other than carotid bodies) sense and respond to changes in carbon dioxide (CO2) concentrations. An increase in the levels of CO2 (hypercapnia) is often a consequence of impaired gas exchange in lung diseases such as chronic obstructive pulmonary disease (COPD) and others. Approximately 17 million individuals in the US are afflicted by COPD, which now is the 3rd leading cause of overall mortality worldwide. Several studies have reported that patients with COPD and hypercapnia have worse outcomes. However, hypercapnia in patients with lung diseases is largely tolerated as there is still the notion that the effects of hypercapnia are not harmful to the lungs. Recent studies, including our own, have demonstrated that elevations in CO2 activate specific intracellular signaling pathways with adverse consequences for lung and organismal functions. We have conducted experiment using unbiased, hypotheses-generating, as well as hypotheses-driven approaches, which have generated preliminary data on the effects of hypercapnia on the lungs airways. Our preliminary results in preparation for this grant application suggest that high CO2 levels activate specific signaling pathways leading to changes in airway contractility. As such, we propose to elucidate the signaling pathways and mechanisms by which hypercapnia increases airway contractility and smooth muscle cell function via three interrelated specific aims. In experiments pertaining specific aim 1, we will determine whether hypercapnia increases airway smooth muscle contraction via activation of caspase-7 and downregulation of miR-133a-MEF2D. In studies pertaining specific aim 2, we will determine whether hypercapnia increases actin polymerization and thus airway smooth muscle contractility via RhoA and calcineurin and in studies pertaining specific aim 3, we will determine hypercapnia promotes airway remodeling by increasing αSMA and extracellular matrix via RhoA-SRF and/or Wnt-CTGF pathway. Completion of the proposed experiments will provide novel information on signaling pathways and mechanisms by which high CO2 levels lead to lung airways hyperreactivity, which is of importance for patients with chronic lung diseases such as COPD and hypercapnia.

项目概要氧气和一氧化氮激活细胞信号传导途径，这对肺部健康很重要然而，人们对肺细胞（其他细胞）的机制知之甚少。比颈动脉体）感知二氧化碳 (CO2) 浓度的变化并做出反应。二氧化碳水平升高（高碳酸血症）通常是体内气体交换受损的结果肺部疾病，例如慢性阻塞性肺病（COPD）等。美国约有 1700 万人患有慢性阻塞性肺病 (COPD)，目前已成为第三大慢性阻塞性肺病 (COPD) 几项研究报告称，患有以下疾病的患者是全球总体死亡的主要原因。慢性阻塞性肺病（COPD）和高碳酸血症的结果更差，但肺病患者的高碳酸血症。疾病在很大程度上是可以耐受的，因为仍然存在这样的观念：高碳酸血症的影响不会最近的研究（包括我们自己的研究）已经证明，升高对肺部有害。 CO2 激活特定的细胞内信号通路，对肺和肺部产生不良后果我们使用无偏见的、生成假设的实验进行了实验。以及假设驱动的方法，这些方法已经生成了有关影响的初步数据我们为这项拨款做准备的初步结果。应用表明，高二氧化碳水平会激活特定的信号通路，从而导致变化因此，我们建议阐明信号通路和高碳酸血症增加气道收缩力和平滑肌细胞的机制在有关特定目标 1 的实验中，我们将通过三个相互关联的特定目标发挥作用。确定高碳酸血症是否会增加气道平滑肌收缩相关研究中 caspase-7 的激活和 miR-133a-MEF2D 的下调。具体目标2，我们将确定高碳酸血症是否会增加肌动蛋白聚合因此通过 RhoA 和钙调神经磷酸酶实现气道平滑肌收缩，并在研究中关于具体目标 3，我们将确定高碳酸血症通过以下方式促进气道重塑：通过 RhoA-SRF 和/或 Wnt-CTGF 途径增加 αSMA 和细胞外基质。完成拟议的实验将提供有关信号通路的新信息以及高二氧化碳水平导致肺气道过度反应的机制，这是对于慢性阻塞性肺病和高碳酸血症等慢性肺部疾病患者的重要性。