With >1014 oxidants/puff, cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), the 4th cause of mortality in the US. Central to COPD pathogenesis is """"""""ciliopathy"""""""", dysfunction of the airway ciliated cells that mediate transport of mucus to remove inhaled pathogens. The COPD ciliopathy leads to mucus accumulation, impaired host defense and recurrent infections. Using a state-of-the-art platform for global metabolite profiling and unique cohorts with serum and lung biologic samples, our deliverables are to identify a metabolome focused on biomarkers related to airway ciliopathy in COPD, and use the observed metabolic changes to: (1) direct mechanistic studies to define ciliopathy at a molecular level;(2) identify novel targets for therapeutic intervention in COPD;and (3) identify smokers at high risk for COPD. Preliminary metabolic data led to our first clues - COPD smokers have decreased serum citrulline levels, consistent with a deficiency in lung nitric oxide synthase (NOS) activity, and thus lung nitric oxide (NO) deficiency. This, together with supporting data of a smoking-induced NOS/NO-related ciliopathy, and knowledge that smokers have significant oxidant-related changes in the airway epithelial transcriptome, led to our aims, combining metabolomics of defined cohorts, murine and human mechanistic studies and computational / statistical integration.
Aim 1. To carry out metabolic profiling of banked biologic samples from our characterized cohorts to assess the hypothesis that smoking-induced COPD is associated with a unique metabolome in serum and lung ELF, and that subsets of the COPD metabolome are linked to the ciliopathy of COPD.
Aim 2. To combine metabolic profiling and in vitro studies of human and murine airway epithelium to evaluate the hypothesis that there is a link between the COPD metabolome (focusing on the inferred NO deficiency) and mechanisms underlying the ciliopathy of COPD.
Aim 3. Characterize and quantify the cigarette smoke induced """"""""redoxome"""""""" in lung and serum and assess its role in ciliated cell dysfunction. Studies seek to identify a link between smoking, burden of oxidants to the lung epithelium and the pathogenesis of COPD - potentially providing biomarker(s) that predict which smokers will develop COPD and identifying new targets for therapy of COPD.
COPD, the smoking-mediated 4th cause of death in the US, is characterized by airway ciliated cell dysfunction (ciliopathy) and susceptibility to recurrent respiratory infections. We propose a combination of metabolomic and mechanistic studies to discovery novel biomarkers that predict which smokers will develop COPD and to identify new targets for the therapy of COPD. (End of Abstract)
|Podgorny, Oleg; Peunova, Natalia; Enikolopov, Grigori (2018) Tracing dividing stem cells. Aging (Albany NY) 10:1534-1535|
|Staudt, Michelle R; Salit, Jacqueline; Kaner, Robert J et al. (2018) Altered lung biology of healthy never smokers following acute inhalation of E-cigarettes. Respir Res 19:78|
|O'Beirne, Sarah L; Shenoy, Sushila A; Salit, Jacqueline et al. (2018) Ambient Pollution-related Reprogramming of the Human Small Airway Epithelial Transcriptome. Am J Respir Crit Care Med 198:1413-1422|
|Gomi, Kazunori; Tang, Yongjiang; Arbelaez, Vanessa et al. (2017) Endothelial Cell Mediated Promotion of Ciliated Cell Differentiation of Human Airway Basal Cells via Insulin and Insulin-Like Growth Factor 1 Receptor Mediated Signaling. Stem Cell Rev 13:309-317|
|Zhou, Haixia; Brekman, Angelika; Zuo, Wu-Lin et al. (2016) POU2AF1 Functions in the Human Airway Epithelium To Regulate Expression of Host Defense Genes. J Immunol 196:3159-67|
|Strulovici-Barel, Yael; Shaykhiev, Renat; Salit, Jacqueline et al. (2016) Pulmonary Abnormalities in Young, Light-Use Waterpipe (Hookah) Smokers. Am J Respir Crit Care Med 194:587-95|
|Tilley, Ann E; Staudt, Michelle R; Salit, Jacqueline et al. (2016) Cigarette Smoking Induces Changes in Airway Epithelial Expression of Genes Associated with Monogenic Lung Disorders. Am J Respir Crit Care Med 193:215-7|
|Gomi, Kazunori; Staudt, Michelle R; Salit, Jacqueline et al. (2016) JAG1-Mediated Notch Signaling Regulates Secretory Cell Differentiation of the Human Airway Epithelium. Stem Cell Rev 12:454-63|
|Deeb, Ruba S; Walters, Matthew S; Strulovici-Barel, Yael et al. (2016) Smoking-Associated Disordering of the Airway Basal Stem/Progenitor Cell Metabotype. Am J Respir Cell Mol Biol 54:231-40|
|Chen, Qiuying; Deeb, Ruba S; Ma, Yuliang et al. (2015) Serum Metabolite Biomarkers Discriminate Healthy Smokers from COPD Smokers. PLoS One 10:e0143937|
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