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44 45 > Research Report // AR 2006
Dysregulation of normal muscle function and its
contribution to the development of fatty liver disease.
The liver plays a central role in processing macronutrients
in response to the influx of nutrients and hormones such
as insulin. While the liver maintains fasting blood glucose
concentrations, skeletal muscle and fat tissue are the major
sites of insulin stimulated glucose disposal. Furthermore,
muscle is intricately involved in whole body lipid (fat)
homeostasis. In these additional studies, we examined
changes in the expression of key genes regulating energy
uncoupling, lipid oxidation and glucose transport in the
muscle and liver of mice that develop NASH when fed a
diet deficient in the compounds methionine and choline
(MCD). Our results indicated that lipid oxidation in muscle
is reduced during MCD feeding, thereby delivering a higher
lipid load to the liver and contributing to the development
of hepatic steatosis. Thus, there appears to be a complex and
intricate link between the liver and muscle with regard to
lipid homeostasis that may in part explain lipid accumulation
in the livers of persons who develop fatty liver disease.
The role of the hormone adiponectin and its receptors in
hepatic fibrosis
Liver injury from any cause can lead to hepatic fibrosis, a
process which is mediated by the hepatic stellate cell (HSC).
Adiponectin, a recently characterised hormone secreted
by fat cells with anti-inflammatory and anti-atherogenic
properties may serve as a novel protein in the modulation
of liver fibrosis. Researchers at the Storr Liver unit became
interested in this protein when we noted that low levels
of adiponectin were associated with the development of
NASH in humans. In contrast, high levels of this hormone
appear to be protective for the development of a fatty
liver. We therefore sought to characterise the modulation
of adiponectin receptors which mediate the function of
adiponectin during the activation of HSCs to a profibrogenic
cell type. While this project is in its infancy, we have
demonstrated significant decreases in the expression levels
of the AdipoR1 but not the AdipoR2 receptor during the
activation of HSCs. In contrast, when HSCs were treated
with the cytokine transforming growth factor beta, the
expression of AdipoR2 was up-regulated. Our results indicate
that differential modulation of adiponectin receptors occurs
in vitro during HSC culture and in response to profibrogenic
cytokines. These changes in receptor expression may play
an important role in modulating the fibrogenic response
of the liver to chronic injury. Further studies are therefore
underway to determine the molecular basis of these effects
and to determine if modulation of these receptors in the liver
can lead to reductions in hepatic fibrosis in patients with fatty
liver disease.
Molecular pharmacology research
The Molecular Pharmacology group, lead by Professor Chris
Liddle is engaged in research into the mechanisms regulating
the metabolism and transport of both xenobiotic compounds
(such as therapeutic drugs) and endobiotics (such as lipids,
cholesterol and bile acids) within the liver. Nuclear receptors
are key intracellular proteins that “sense” the presence of
these molecules and they have been working to exploit these
receptors as targets to develop new treatments for a range
of liver diseases. Parts of this work are being performed in
collaboration with the laboratory of Professor Ron Evans at
the Salk Institute, La Jolla, California. In collaboration with
the Cancer Pharmacology Unit at Concord Hospital we
have been investigating the altered metabolism of drugs that
frequently occurs in patients with advanced cancer with a
view to developing interventions that will allow such patients
to be able to receive the benefit of full doses of vital cancer
chemotherapy. Our recent work in the field of regulatory
mechanisms in drug metabolism has led to the generation
of two patents, which have been successfully licensed to the
pharmaceutical industry. Royalties arising from these patents
now provide significant ongoing funding for research projects
with the Storr Liver Unit.
Neuroscience and Vision
Brain Dynamics Centre
Brain connectivity projects
These projects are focused on understanding the mechanisms
of how the brain binds information into a coherent whole,
and determines what is significant and important, and what
is not. Understanding the mechanisms of integrative brain
function is important for identifying the causes of disorders
of mental health.
A second focus of these projects is on the role of age and
sex differences. Major psychiatric disorders have striking
differences in their prevalence in males versus females, and
peak ages of onset, such that understanding these factors is
important for understanding the processes of mental illness.
A PhD thesis on this topic will be completed this year.
Towards a continuum of orienting and defensive responses
This ARC Discovery project is focused on identifying the
neural mechanisms underlying how we determine what is
significant in the environment, and process it accordingly.
The ability to discriminate what is significant and important
from what is not is crucial to effective information processing.
Thus, a breakdown in the mechanism of significance
processing may underlie major psychiatric disorders.
PhD research in this area was awarded the Tasman-Lovell
medal this year for the best project.
Development of integrative markers of brain function
This is another ARC linkage project and is focused on
integrating genetic information with cognitive, emotional
and neuroimaging measures to identify evidence-based
biological markers of complex brain function. Biological
markers are important tools for identifying predisposing
factors to disease, diagnosis, treatment evaluation, and the
monitoring of disease progression.
Emotion processing in adolescence and application to
conduct disorder
This project is focused on understanding the biological
basis of emotion processing in adolescence, which is a peak
period for the onset of emotional and behavioural disorders.
These results will provide a platform for identifying specific
disturbances in emotion-related brain function in children
and adolescents with conduct disorder.
Results to date show a striking change in brain function
profile for salient emotions of fear and happiness from
childhood (6-7 years) to adolescence (8-13) years to later
teenage years (14-15 years), when the profile becomes more
like that of an adult
Identifying the ‘signature’ for ADHD and
treatment predictions
This project has used tests of emotion cognition and brain
function to identify objective markers of ADHD and
response to stimulants in ADHD. These markers were found
to classify over 80% of ADHD adolescents.
Posttraumatic stress disorder (PTSD) biological markers
and treatment response
This project aims to develop the most effective treatments for
acute and chronic PTSD. Cognitive behavioural treatments
(CBT) are the current first line treatment of PTSD, but
response can be heterogeneous. This project aims to identify
the most effective elements of CBT treatment of PTSD.
The group conducted a randomized controlled trial on
103 participants with PTSD to examine the most effective
combination of treatment elements for PTSD. Specifically,
the group examined whether cognitive therapy (CT)
enhanced treatment response to exposure-based therapies
(prolonged (PE) and invivo (IV) in an 8-week CBT program
conducted in the Clinic for Traumatic Stress at BDC.
Acute stress disorder treatment efficacy
This study examined the relative efficacy of cognitive therapy
(CT) and exposure treatments in acute trauma populations
(within 3-4 weeks of trauma) in a randomized controlled
trial. Results indicate that early intervention following trauma