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Duane
Smoot,
M.D.
Principal
Investigator,
Howard University
Hospital
dsmoot@howard.edu
ABSTRACT
Chronic
ethanol
ingestion
is responsible
for 70
to 80
percent
of the
cases
of chronic
pancreatitis.
However,
the mechanism(s)
by which
ethanol
causes
pancreatitis
is not
known.
Only
five
to ten
percent
of alcoholics
develop
pancreatitis,
which
would
suggest
that
factors
other
than
the
amount
or
type
of alcohol
ingested
is important
in the
development
of this
disease.
Pancreatitis
is a
disorder
of the
exocrine
pancreas
with
processes
of inflammation
and parenchymal
cell
death.
Models
of
experimental
pancreatitis show
that
the types
of cell
death
include
both apoptosis
in the
pancreatic
acinar
cells
of the
pancreas.
For
the present
project
we hypothesize
that
ethanol
and /or
its metabolite
cause
apoptosis
and necrosis
cell
death
in pancreatic
acinar
cells
by regulating
pathways
involving
caspases
and mitochondrial
depolarization.
We further
postulate
that
the effect
of ethanol
and/or
its metabolites
on the
cell
death
processes
occurs
through
their
ability
to modulate
the caspase
and mitochondrial
responses
to neurohumoral
agents (i.e.
cholecystokinin
and acetylcholine)
and cytokines
(i.e.
TNPα).
The
studies
proposed
in this
grant
application
are designed
to determine
the effect
of ethanol
and its
metabolites
on apoptosis
and necrosis
and the
pathways
that
regulate
these
processes
in pancreatic
acinar
cells
in order
to further
elucidate
the mechanism
of alcoholic
pancreatitis.
The specific
aims
of this
proposal
are:
- Determine
the
effect
of
ethanol,
acetaldehyde
and
fatty
acid
ethyl
ester
treatments
of
dispersed
pancreatic
acini
from
rats
incubated
in
the
presence
and
absence
of
cholecystokinin
or
TNF-α on
apoptosis
and
necrosis
rates,
initiator
and
effector
caspase
activation,
mitochondrial
polarity
and
mitochondrial
cytochrome
c
release;
- Measure
apoptosis
and
necrosis
rates,
initiator
and
effector
caspase
activation,
mitochondrial
polarity
and
mitochondrial
cytochrome
c
release
in
the
pancreas
from
rates
after
the
initiation
of
experimental "acute" or "chronic" pancreatitis
with
parenteral
infusions
of
cholecystokinin
analogues;
- Determine
the
roles
of
nuclear
factor-κB
(NF-κB)
and
poly
(ADP-ribose)
polymerase
(PARP)
in
regulating
the
effects
of
ethanol
and
its
metabolites
on
apoptosis
and
necrosis
rates
as
well
as
the
caspase
and
mitochondrial
pathways
that
mediate
the effects.
The
project
described
in this
application
is designed
to elucidate
the effects
ethanol
and its
metabolites
on the
various
components
of these
pathways
regulating
apoptosis
and necrosis
using
in vivo
models
of experimental
acute
and chronic
pancreatitis
as well
as in
vitro
cultures
of pancreatic
acini.
The results
should provide
insights
into
strategies
that
can be
developed
to ameliorate
the severity
of pancreatitis
due to
alcohol
abuse.
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