The long-term goal of this project is to identify Fibroblast Growth Factor (FGF) 23 and klotho as potential aging markers in COPD subgroups and develop future therapeutic strategies targeting these pathways. Chronic obstructive pulmonary disease (COPD) currently represents the third leading cause of mortality in North America and the majority of cases are caused by cigarette smoke. Both clinical and cellular evidence support the concept that accelerated lung aging serves as an underlying mechanism for its pathogenesis. We have good in vitro models and in vivo models to analyze the crosstalk between FGF23 and klotho and their effect on cell senescence in the airway epithelium. In addition, we will employ the COPDGene cohort to translate these findings to determine their relevance in individuals with COPD. Both FGF23 and klotho have been associated with chronic airway inflammation and accelerated aging in COPD and we hypothesize that a dysregulated klotho/FGF23 ?rheostat? contributes to airway epithelial cell senescence. We therefore propose to investigate the underlying molecular mechanisms in order to identify future novel therapeutic targets.
Aim 1 will investigate the impact of increased FGF23 signaling on airway epithelial cell senescence by primary human airway epithelial cell cultures and mice, deficient in klotho or overexpressing klotho and expose them to cigarette smoke FGF23.
Aim 2 will determine the underlying molecular mechanisms on accelerated airway aging in individuals with COPD and characterize klotho and FGF23 as prognostic aging markers by using the COPDGene cohort with access to plasma samples and de-identified clinical data. Overall, this proposal will identify a novel pathway involved in airway epithelial cell senescence leading to smoke induced lung diseases such as COPD and therefore open novel therapeutic options in diseases that are on the rise due to an aging population.

Public Health Relevance

The goal of this project is to identify novel signaling pathways contributing to airway epithelial cell senescence in chronic obstructive pulmonary disease. Due to increasing life expectancy in combination with exposure to environmental pollutants and cigarette smoke, COPD is becoming a rising problem and therefore, novel therapeutic approaches, ?anti-aging strategies?, are needed. We propose a translational approach to investigate signaling pathways of two proteins and their crosstalk: 1) Fibroblast Growth Factor 23, a pro- inflammatory circulating marker, which has been associated with systemic inflammation and COPD and 2) klotho, an ?anti-aging? hormone, which is downregulated in COPD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Research Grants (R03)
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Special Emphasis Panel (ZAG1)
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Williams, John
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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