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-/- (M?-NLRX1-/-) and macrophage-specific NLRX1 transgenic overexpression (M?-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.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) remains as a major cause of health burden, yet without a single pharmaceutical modality that can reduce disease progression. The goal of this grant is to define the roles of novel mitochondrial molecules called NLRX1 and PINK1 in the development of COPD. In addition, we will explore in a murine COPD model whether interventions that restore suppressed NLRX1 or modulate this pathway have therapeutic potential.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL130283-01A1
Application #
9175689
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Postow, Lisa
Project Start
2016-07-01
Project End
2020-03-31
Budget Start
2016-07-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
$418,750
Indirect Cost
$168,750
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520