Role of NLRX1 in cigarette smoke-induced pulmonary inflammation and remodeling

NLRX1 在香烟烟雾诱导的肺部炎症和重塑中的作用

基本信息

批准号：
9175689
负责人：
Min-Jong Kang
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9175689
关键词：
Address Air Alveolar Macrophages Apoptotic Attenuated Binding CASP1 gene Cell Death Cells Characteristics Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Clinical Clinical Research DNA Damage Development Disease Disease Progression Disease model Ensure Excision Gene Delivery Goals Grant Health Human Inflammatory Interleukin-18 Intervention Leucine-Rich Repeat Lung Mediating Medical Metalloproteases Mitochondria Mitochondrial Proteins Modality Monitor Mus Mutant Strains Mice Nucleotides Organelles PTEN gene Pathogenesis Pathway interactions Patients Peptides Pharmacologic Substance Phenotype Phosphotransferases Play Population Proteins Pulmonary Emphysema Pulmonary Inflammation Quality Control Reactive Oxygen Species Research Role Severities Smoking Stress Structure of parenchyma of lung Syndrome Testing Therapeutic Transgenic Organisms Wild Type Mouse base cigarette smoke-induced cigarette smoking cohort environmental tobacco smoke exposure in vivo inhibitor/antagonist macrophage non-smoker novel novel therapeutics overexpression response restoration

项目摘要

Project Summary Chronic obstructive pulmonary disease (COPD) encompasses several clinical syndromes, most notably emphysema and chronic bronchitis. It is a major unmet medical need in human health and is strongly associated with cigarette smoke (CS) exposure. Most of the current treatments, however, fail to attenuate severity and progression of the disease, thereby requiring better mechanistic understandings of pathogenesis to develop disease-modifying therapeutics. We recently demonstrated that the nucleotide-binding domain and leucine-rich-repeat-containing protein X1 (NLRX1), a novel mitochondrial molecule, plays an important inhibitory role in the pathogenesis of COPD. The importance of NLXR1 was also evident in clinical studies. From three independent human COPD cohorts, the expression of NLRX1 was suppressed in lungs from patients with COPD and this suppression showed strong correlation with the degree of airflow limitation, a hallmark of COPD. The current proposal aims to define the underlying mechanism(s) by which the suppression of NLRX1 contributes to the pathogenesis of COPD and to determine the therapeutic potential of NLRX1 restoration in vivo as a disease modifier of COPD. Preliminary studies revealed that (i) pulmonary macrophages were the cell population where the expression of NLRX1 was most prominent in lungs from both non-smokers and no-smoking (NS) control mice; (ii) the expression of NLRX1 was significantly suppressed in pulmonary macrophages from mice exposed to CS; and (iii) importantly, the expression of markers of CS- induced activated macrophages (interleukin (IL)-18, mitochondrial reactive oxygen species (mtROS), metalloproteases (MMPs)) were markedly enhanced in macrophages from NLRX1-/- mice compared to those from WT mice after CS exposure. These results highlight NLRX1 as a critical regulator of CS-induced activation of pulmonary macrophages, a cell population that plays a major role in COPD pathogenesis. Furthermore, we identified that NLRX1 interacts with PTEN-induced kinase 1 (PINK1), a molecule known to have an important role in mitochondrial quality control (MQC). Based on these observations, we hypothesize that NLRX1 plays as a critical inhibitor of CS-induced activation of pulmonary macrophages via PINK1- mediated MQC. To test the hypothesis, we will utilize newly generated mice that harbor macrophage-specific conditional NLRX1-/- (MΦ-NLRX1-/-) and macrophage-specific NLRX1 transgenic overexpression (MΦ-NLRX1 Tg). Proposed aims are as follows: #1. Characterize the effects of CS on the expression of NLRX1 in mice, the alteration of the expression of NLRX1 in patients with COPD, and define the role(s) of macrophage-specific NLRX1 in CS-induced pulmonary inflammation and remodeling responses; #2. Define the alteration of functional characteristics of CS-exposed pulmonary macrophages and the underlying mechanism(s) by which NLRX1 determines these alterations; #3. Determine if restoring the expression of NLRX1 in vivo ameliorates CS-induced pulmonary inflammatory and remodeling responses.

项目概要慢性阻塞性肺疾病 (COPD) 包括多种临床综合征，其中最突出的是肺气肿和慢性支气管炎是人类健康中未满足的重大医疗需求。然而，目前的大多数治疗方法都未能减弱与香烟烟雾（CS）暴露有关的症状。疾病的严重程度和进展，因此需要更好地了解发病机制我们最近证明了核苷酸结合域和富含亮氨酸重复序列的蛋白 X1 (NLRX1) 是一种新型线粒体分子，在线粒体中发挥着重要作用 NLXR1 在 COPD 发病机制中的抑制作用在临床研究中也很明显。在三个独立的人类 COPD 队列中，NLRX1 的表达在肺中受到抑制患有慢性阻塞性肺病（COPD）的患者，这种抑制与气流受限的程度有很强的相关性，当前提案旨在定义抑制的基本机制。 NLRX1 有助于 COPD 的发病机制并确定 NLRX1 的治疗潜力体内恢复作为慢性阻塞性肺病的疾病调节剂，初步研究表明（i）肺部。巨噬细胞是 NLRX1 在肺中表达最显着的细胞群非吸烟者和不吸烟（NS）对照小鼠；（ii）NLRX1 的表达在暴露于 CS 的小鼠的肺巨噬细胞；以及 (iii) 重要的是，CS-标记物的表达诱导巨噬细胞（白细胞介素 (IL)-18、线粒体活性氧 (mtROS)、与那些小鼠相比，NLRX1-/-小鼠的巨噬细胞中的金属蛋白酶（MMP）显着增强来自 CS 暴露后的 WT 小鼠，这些结果强调了 NLRX1 作为 CS 诱导的关键调节因子。肺巨噬细胞的激活，这是一种在慢性阻塞性肺病发病机制中起主要作用的细胞群。此外，我们还发现 NLRX1 与 PTEN 诱导的激酶 1 (PINK1) 相互作用，这是一种已知的分子在线粒体质量控制（MQC）中具有重要作用。 NLRX1 通过 PINK1 作为 CS 诱导的肺巨噬细胞激活的关键抑制剂为了验证这一假设，我们将利用新生成的具有巨噬细胞特异性的小鼠。条件性 NLRX1-/- (MΦ-NLRX1-/-) 和巨噬细胞特异性 NLRX1 转基因过表达 (MΦ-NLRX1 Tg）。建议的目标如下：#1。描述 CS 对小鼠 NLRX1 表达的影响。 COPD 患者中 NLRX1 表达的改变，并确定巨噬细胞特异性的作用 NLRX1 在 CS 诱导的肺部炎症和重塑反应中的作用；定义 #2 的改变。 CS暴露的肺巨噬细胞的功能特征及其潜在机制 #3. 确定恢复体内 NLRX1 的表达是否会改善 CS 诱导的肺部炎症和重塑反应。