The development of more effective anti-inflammatory/analgesic drugs depends on a better
understanding of the mediators involved in inflammation and pain pathways. Recently,
proteases and the receptors they activate: Prot
ease-Activated Receptors (PARs) have been
identified as important mediators in inflamma
tory and pain reactions in animal models.
Definitive studies need now to investigate the role of those mediators in human diseases. We
the hypothesis that proteases, through the activation of PARs, play a major role in
chronic human inflammatory diseases, particip
ating to the generati
on of inflammatory
and pain symptoms.
Inflammatory Bowel Diseases (IBD) such as
Crohn's disease or Ulce
rative colitis afflict
millions of patients, leaving those patients
with poor quality of li
fe and chronic pain
symptoms. Curative therapies for IBD remain
elusive, because the mechanisms involved in
the pathogenesis of IBD are not
fully understood. We have show
n in animal models of IBD
that proteases, through the activation of PARs
play a major role in the generation of
inflammatory and pain symptoms.
Now, we propose to define th
e role of proteases and PARs
in the human disease.
-We propose to investigate the pr
oteolytic activity and
types of proteases re
leased by tissues
from IBD patients.
-We propose to investigate the effects of mediat
ors released by tissues from IBD patients on
the activation of all members of the PAR family (PAR
-We propose to investigate the effects and th
e mechanisms by which
released by tissues from IBD patients, can i
nduce inflammation and pai
n, using both a cellular
approach (culture of monocytic cells, epit
helial cells and sensory neurons), and an
approach (induction of colitis in mice). Comp
letion of these studies should clarify the
importance of proteases in human inflammatory
diseases and could have direct implications
on therapeutic development, by defining pot
ential new targets for drug development.
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
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