Omar Tliba | Editor
Affilation: Long Island University, USA
Use ASM cells as a model to gain mechanistic insight in the development of steroid insensitivity in severe asthma: While much research aimed at understanding the basis of insensitivity to glucocorticoid therapy in severe asthmatics focused on the role of immune cells, little has been done to clarify the role of ASM cells. Recent studies performed on bronchial biopsies from asthmatics treated with inhaled or oral glucocorticoids showed a persistent expression of chemokines in ASM bundles. The expression of these genes correlated with the severity of asthma. Our previous studies replicated this finding in vitro using cultured human ASM cells. The induction of pro-asthmatic genes is less sensitive to inhibition by glucocorticoids when such induction was triggered by TNF and IFN combination. We will use ASM as a model to further define the mechanisms involved in steroid insensitivity.
Characterize the mechanisms that regulate glucocorticoid receptor phosphorylation with a primary focus on the role of Mitogen-Activated Protein Kinase (MAPK) pathways and serine/threonine protein phosphatases (PPs): Phosphorylation of glucocorticoid receptor (GR) on various residues such as serine 203 (S203), S211, and S226 plays a key role in determining the strength and duration of GR actions. At present, uncertainty still exists about the nature of the GR phosphorylation-dependent mechanisms regulating the overall cellular responsiveness to glucocorticoid and which particular GR phosphorylation profile is associated with steroid insensitive conditions. We are using various molecular, biochemical, and cellular strategies to better characterize the role of Mitogen-Activated Protein Kinase (MAPK) pathways and serine/threonine protein phosphatases (PPs) that regulate GR phosphorylation, and thus function, in airway cells with a long-term goal of providing new insight into therapies aiming at restoring steroid responsiveness in patients with severe asthma.
Expression and function of glucocorticoid-target genes in airway cells: These studies involve collaborations with a number of investigators and are focused on evaluating the biological role of steroid-target genes in airway cells both in vivo and in vitro using endobronchial tissues isolated from asthmatics with varying degrees of disease severity. Our long-term goal is to integrate the biological effects of such genes in the evaluation of inhaled glucocorticoids efficacy in asthmatic patients.
Transcriptional regulation of cytokine functions in airway cells: ASM cells respond to many cytokines, growth factors and lipid mediators to produce a wide array of immuno-modulatory molecules which may in turn orchestrate and perpetuate the disease process in asthma. Our goals are to identify intracellular signaling pathways by which cytokines modulate or induce these cellular responses. A focus of this project is to investigate the transcriptional and post-transcriptional mechanisms regulating cytokine functions in ASM cells