1) Bench to Bedside (Translational Project): Airway
hyper-responsiveness (or exaggerated airway narrowing)
is a defined characteristic of asthma that explains many
of its clinical features especially in severe states.
Using different models (isolated cells and airway tissues)
and various experimental approaches (cellular and molecular),
our current studies are trying to elucidate how inflammatory
cytokines modulate contractile and relaxant functions
of airway smooth muscle with a particular emphasis on
calcium metabolism and RhoA/Rho kinase pathways.
Kim JH, Jain D, Tliba O, Yang B, Jester, WF Jr., Panettieri,
RA Jr., Amrani Y & and Ellen Puré. TGFß
potentiates airway smooth muscle responsiveness to bradykinin.
Am J. Physiol. Lung. 289(4):L511-20, 2005.
Chen H, Tliba O., Van Besien C.R., Panettieri, R.A. Jr.
and Amrani Y. TNF? modulates Murine Tracheal Rings responsiveness
to GPCR agonists and KCl. J. Appl. Physiol. 95: 864-872,
2003.
Amrani Y, Tliba O, Deshpande DA, Walseth TF, Kannan MS
and Panettieri, RA Jr. Bronchial hyper-responsiveness:
Insights into new signaling molecules. Cur Opin Pharmacol.,
4:230-234, 2004.
2) Bench to Bedside (Translational Project): Although
corticosteroids are the most effective anti-inflammatory
drugs to treat chronic lung diseases, there are still
a number of patients that do not respond to steroid treatment.
Steroid resistance is a veritable health challenge due
to the absence of therapeutic alternatives and a financial
burden as steroid-resistant patients account for more
than 50% of health care total costs. In collaboration
with Dr. Cidlowski, we are trying to provide new insight
into the molecular mechanisms that promote steroid resistance
or reduce steroid function in lung cells.
Tliba O, Cidlowski J, Amrani Y. CD38 expression is insensitive
to steroid action in cells treated with TNF{alpha} and
IFN{gamma} by a mechanism involving the upregulation of
glucocorticoid receptor {beta} isoform. Mol Pharmacol.
Feb;69(2):588-96, 2006
3) Bench to Bedside (Translational Project): Signaling
pathways regulating the expression of inflammatory genes
associated with lung diseases, asthma and COPD. Inflammation
is a central feature of asthma. A better understanding
of the molecular mechanisms that orchestrate and/or perpetuate
the airway inflammation will likely provide new ways to
treat asthma. Dr. Amrani is currently trying to identify
(i) the factors (inflammatory cytokines, GPCR agonists),
(ii) the receptor-associated signal transduction pathways
(transducers, transcription factors, signaling molecules)
and, (iii) the transcriptional and/or post transcriptional
mechanisms that regulate the expression of inflammatory
genes linked to asthma.
Tliba O, Panettieri RA. Jr, Tliba S, Walseth TF and Amrani
Y. TNF? differentially regulates the expression of pro-inflammatory
genes in human airway smooth muscle cells by activation
of IFN?-dependent CD38 pathway. Mol. Pharmacol., 66(2)
322-329, 2004.
Tliba O, Hoffman R, Delong P, Panettieri, RA, Jr and
Amrani Y. TNFa modulates STAT1-Dependent Gene Expression
in human airway myocytes. J. Biol. Chem. 278(50):50615-50623,
2003
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