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.

项目摘要氧气和一氧化氮激活细胞信号通路，这对肺部健康很重要和疾病。但是，关于肺细胞的机制知之甚少（其他比颈动脉身体）有意义，并应对二氧化碳（CO2）浓度的变化。一个二氧化碳水平（Hypercapnia）的水平增加通常是气体交换受损的结果肺部疾病，例如慢性阻塞性肺疾病（COPD）等。在美国，大约有1700万个人受到COPD的困扰，这是第三名全球总体死亡率的主要原因。几项研究报告说患者 COPD和Hypercapnia的结果较差。然而，肺患者的高碳酸血症疾病在很大程度上被耐受性，因为仍然有这样的观念认为超脑的影响不是对肺有害。最近的研究，包括我们自己的研究表明 CO2激活特定的细胞内信号通路，对肺和肺部和有机功能。我们已经使用公正的，假设生成的实验，以及假设驱动的方法，这些方法已经产生了有关效果的初步数据肺部气道上的高碳酸盐。我们为这笔赠款做准备的初步结果应用表明，高二氧化碳水平激活特定的信号通路，导致变化在气道收缩性中。因此，我们建议阐明信号通路和高碳酸脂蛋白增加气道收缩力和平滑肌细胞的机制通过三个相互关联的特定目标来函数。在针对特定目标1的实验中，我们将确定高碳酸脂蛋白是否通过通过 caspase-7的激活和miR-133a-mef2d的下调。在研究中具体目标2，我们将确定高碳酸血症是否增加肌动蛋白聚合因此，气道通过RhoA和钙调神经酶以及研究关于特定目标3，我们将通过通过RhoA-SRF和/或Wnt-CTGF途径增加αSMA和细胞外基质。提出的实验的完成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高反应性的机制，对于慢性肺部疾病（例如COPD和Hypercapnia）患者的重要性。