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Development of novel therapeutics for stroke : preclinical investigations of osteopontin and...
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Development of novel therapeutics for stroke : preclinical investigations of osteopontin and 3-iodothyronamine.
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http://www.ohsu.edu/xd/education/library/services/theses-dissertations/rights-statement.cfm
Title
Development
of
novel
therapeutics
for
stroke
:
preclinical
investigations
of
osteopontin
and
3-iodothyronamine
.
Creator.PersonalName
Doyle
,
Kristian
Paul
Thesis.Degree
Ph.D.
Thesis.Major
Molecular Microbiology and Immunology
Thesis.DateDegreeAwarded
2007
Institution
Oregon Health & Science University
School
School of Medicine
Department
Dept. of Molecular Microbiology and Immunology
Thesis.Advisor/Mentor
Stenzel-Poore, Mary P.
Thesis.Committee
Grandy, David K.
Heffron, Jeff
Simon, Roger Pancoast
Subject.MeSH
Osteopontin -- therapeutic use
Thyronines -- therapeutic use
Stroke -- therapy
Ischemia -- therapy
Hypothermia, Induced
Neuroprotective Agents -- therapeutic use
Call Number
Q171 D753 2007
Description.Abstract
The
goal
of
my
research
has been to
develop
new
treatments
for
ischemic
stroke
. In
pursuit
of this
goal
I
have
performed
a
preclinical
investigation
of
osteopontin
(OPN)
and
3-iodothyronamine
(T1AM)
,
two
novel
drug
candidates
that
could
be
developed
into
therapies
for
stroke
patients
.
Osteopontin
(OPN)
is
a
secreted
extracellular
phosphoprotein
involved
in
diverse
biological
functions
,
including
inflammation
,
cell
migration
, and
anti-apoptotic
processes
. In this
thesis
I
investigate
the
neuroprotective
potential
of
OPN
using
both
in
vitro
and in
vivo
models
of
ischemia
.
I
show
that
primary
cortical
neuron
cultures
exposed
to
OPN
are
protected
against
cell
death
from
oxygen
and
glucose
deprivation
(OGD)
and that the
effect
of
OPN
depends
on the
Arg-Gly-Asp
(RGD)
motif
, and an
increase
in
Akt
and
p42/p44
MAPK
phosphorylation
.
Intra-cerebral
ventricular
administration
of
OPN
caused
a
marked
reduction
in
infarct
size
following
transient
middle
cerebral
artery
occlusion
in a
murine
stroke
model
and
together
these
data
suggest
that
OPN
is
a
potent
neuroprotectant
against
ischemic
injury
.
I
sought
to
increase
the
neuroprotective
potency
of
OPN
and
improve
the
method
of
delivery
.
Data
presented
here
shows
that
thrombin
cleavage
of
OPN
improves
its
ability
to
ligate
integrin
receptors
and
improves
its
neuroprotective
capacity
in
models
of
ischemia
.
I
also
tested
whether
OPN
could
be
administered
by
intranasal
administration
and
found
that
OPN
is
efficiently
targeted
to the
brain
via
this
delivery
route
and
confers
robust
protection
against
ischemic
brain
injury
.
OPN
mimetics
based
on the
peptide
sequences
located
N
or
C
terminal
to the
thrombin
cleavage
site
were
generated
and
tested
in
models
of
ischemia
.
Treatment
with
successively
shorter
N
terminal
peptides
and a
phosphorylated
C
terminal
peptide
provided
significant
neuroprotection
against
ischemic
injury
. These
findings
show
that
OPN
mimetics
offer
promise
for
development
into
powerful
new
drugs
for the
treatment
of
stroke
.
Mild
hypothermia
confers
profound
neuroprotection
in
ischemia
.
Two
recently
discovered
natural
derivatives
of
thyroxine
,
3-iodothyronamine
(T1AM)
and
thyronamine
(T0AM)
have been
shown
to
lower
body
temperature
in
rodents
for
several
hours
without
induction
of a
compensatory
homeostatic
response
. Here
I
tested
whether
T1AM-
and
T0AM-induced
hypothermia
protects
against
brain
injury
from
experimental
stroke
.
I
administered
T1AM
and
T0AM
1
hour
after
stroke
to
test
for an
acute
protective
effect
and
2
days
prior
to
stroke
to
test
whether
they
could
be
used
as a
preconditioning
stimulus
.
T1AM
and
T0AM
administration
reduced
body
temperature
from
37oC
to
31oC
.
Mice
given
T1AM
or
T0AM
after
the
ischemic
period
had
significantly
smaller
infarcts
compared
to
controls
.
Mice
preconditioned
with
T1AM
prior
to
ischemia
displayed
significantly
smaller
infarcts
compared
to
controls
.
Pre-
and
post-ischemia
treatments
required
a
drop
in
body
temperature
to
achieve
subsequent
neuroprotection
. These
findings
show
that
T1AM
and
T0AM
, are
potent
neuroprotectants
in
acute
stroke
and
T1AM
can
be
used
as
antecedent
treatment
to
induce
neuroprotection
against
subsequent
ischemia
. The
failure
of any
single
neuroprotectant
to be
advanced
to
clinical
use
has
led
to
considerable
interest
in
combinatorial
therapy
. This
thesis
concludes
with a
combinatorial
experiment
using
both
OPN
and
T1AM
with
T1AM
applied
as an
antecedent
treatment
and
OPN
as an
acute
neuroprotectant
.
Language
eng
Type
Text
Format.Use
Needs Adobe Acrobat to view
Format.FileSize
2168867 Bytes
OCLC number
173988220
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