Omar Tliba, Ph.D.
Associate Professor Division of Pulmonary and Critical Care MedicineRobert Wood Johnson Medical School
Rutgers Institute for Translational
Medicine and Science Child Health Institute of New Jersey Rutgers, The State University of New
Jersey 89 French Street
New Brunswick, NJ 08901
Fax: (732) 235-7178
Ms, Biomedical Sciences, University of Rennes I, France
Ms, Immunology, Institut pasteur, Paris
Ph.D., Immunology, University of Francois Rabellais, Tours, France
University of Pennsylvania, Philadelphia, PA
The recent therapeutic
benefit in severe asthmatics provided by bronchial thermoplasty, a therapy that
attenuates bronchoconstriction via reduction of airway smooth muscle (ASM)
mass, has strongly supported the notion that ASM is a key player in the
pathogenesis of asthma. ASM could also participate in the progression of asthma
by secreting pro-inflammatory mediators reported both in cultured cells and in
bronchial biopsies. My research interest includes airway smooth muscle biology,
glucocorticoid signaling, and glucocorticoid resistance. Current research
efforts are focused in four major areas:
- 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.
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.
O'Connell D, Bouazza B, Kokalari B, Amrani Y, Khatib A, Ganther JD, Tliba O. IFN-?-induced JAK/STAT, but not NF-KB, signaling pathway is insensitive
to glucocorticoid in airway epithelial cells. Am J Physiol Lung Cell Mol
Physiol. 2015 Aug 15;309(4):L348-59
Chachi L, Gavrila A, Tliba O, Amrani Y. Abnormal corticosteroid signalling in airway smooth muscle: mechanisms and perspectives for the treatment of severe asthma. Clin Exp Allergy. 2015 Nov;45(11):1637-46.
Gavrila A, Chachi L, Tliba O, Brightling C, Amrani Y. Effect of the plant derivative Compound A on the production of corticosteroid-resistant chemokines in airway smooth muscle cells. Am J Respir Cell Mol Biol. 2015 Nov;53(5):728-37.
Bouazza B, Debba-Pavard M, Amrani Y, Isaacs L, O'Connell D, Ahamed S, Formella D, Tliba O. Basal p38 mitogen-activated protein kinase regulates unliganded glucocorticoid receptor function in airway smooth muscle cells. Am J Respir Cell Mol Biol. 2014 Feb;50(2):301-15.
Chachi L, Shikotra A, Duffy SM, Tliba O, Brightling C, Bradding P, Amrani Y. Functional KCa3.1 channels regulate steroid insensitivity in bronchial smooth muscle cells. J Immunol. 2013 Sep 1;191(5):2624-36.
Bouazza B, Krytska K, Debba-Pavard M, Amrani Y, Honkanen RE, Tran J, Tliba O. Cytokines alter glucocorticoid receptor phosphorylation in airway cells: role of phosphatases. Am J Respir Cell Mol Biol. 2012 Oct;47(4):464-73.
Durham A, Adcock IM, Tliba O. Steroid resistance in severe asthma: current mechanisms and future treatment. Curr Pharm Des. 2011;17(7):674-84. Review.
Damera G, Fogle HW, Lim P, Goncharova EA, Zhao H, Banerjee A, Tliba O, Krymskaya VP, Panettieri RA Jr. Vitamin D inhibits growth of human airway smooth muscle cells
through growth factor-induced phosphorylation of retinoblastoma protein
and checkpoint kinase 1. Br J Pharmacol. 2009 Nov;158(6):1429-41.
Bhandare R, Damera G, Banerjee A, Flammer JR, Keslacy S, Rogatsky I, Panettieri RA, Amrani Y, Tliba O. Glucocorticoid receptor interacting protein-1 restores
glucocorticoid responsiveness in steroid-resistant airway structural
cells. Am J Respir Cell Mol Biol. 2010 Jan;42(1):9-15.
- Goncharova EA, Goncharov DA, Damera G, Tliba O, Amrani Y, Panettieri RA Jr, Krymskaya VP. Signal transducer and activator of transcription 3 is required for
abnormal proliferation and survival of TSC2-deficient cells: relevance
to pulmonary lymphangioleiomyomatosis. Mol Pharmacol. 2009 Oct;76(4):766-77.