DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) is a prevalent fatal disease, defined by a functional defect, that of an irreversible obstruction of airflow from the lungs. We have recently identified a novel role for ceramides in the lung as a central mediator of alveolar cell apoptosis and emphysema. Signaling sphingolipids are essential for ensuring an optimal balance of cell death (ceramides) / survival (sphingosine-1-phosphate, S1P) in tissues. We hypothesize that lungs of patients with emphysema have an increased ceramide / S1P ratio compared to non-diseased lungs. Furthermore, the pattern of ceramide molecular species expression may correlate with the COPD disease phenotype. Those hypotheses will be tested in a proof-of-concept study using tissues and plasma samples from COPD patients and healthy volunteers provided by Lung Tissue Research Consortium, NIH (LTRC). Specifically: the aims of this project are - Aim #1: To determine whether ceramide/S1P ratio is increased in the LTRC lung parenchyma samples obtained from volunteers with COPD compared to those without lung disease. Aim #2: To determine which enzymatic pathways responsible for the ceramide/S1P homeostasis are dysregulated in the LTRC lung parenchyma samples obtained from volunteers with emphysema. Aim #3: To establish whether a distinct ceramide species profile present in the lung parenchyma is recapitulated in the plasma obtained from individuals with a specific COPD phenotype. Together, the studies proposed are expected to improve our understanding of emphysema pathobiology and, importantly, to position sphingolipid signaling as a potential therapeutic target and/or biomarker of emphysema. (End of Abstract) PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Pulmonary emphysema and chronic bronchitis comprise the spectrum of COPD, a prevalent fatal disease. In contrast to chronic bronchitis, which is a disease of chronic inflammation of large airways with increased mucus production, emphysema is characterized by loss of both matrix and cellular elements of the lung, thus impairing gas exchange between the alveolar space and the capillary blood. Although the environmental inducers in susceptible individuals have been identified, the mechanisms by which these initiate a loss of alveoli leading to emphysema are poorly understood. We suggest that COPD is accompanied by the increase in tissue level of ceramides, a potent endogenous inducers if apoptosis. This proof-of-concept project will extend our preliminary observations demonstrating a link between emphysema development and sphingolipid metabolism resulting in accumulation of tissue ceramides by direct comparison of tissue and plasma samples from COPD patients and healthy volunteers provided to us by Lung Tissue Research Consortium (LTRC, NIH). This work may contribute to the discovery of targets for therapy in emphysema and to the development of biological markers for this disease.
|Effective start/end date||9/19/08 → 7/31/11|
- National Institutes of Health: $51,603.00
- National Institutes of Health: $32,750.00
- National Institutes of Health: $84,854.00