Associate Professor Xu-Feng Huang, Dr Leonard Storlien, Associate
Professor Peter McLennan
2002 $
2003 $
2004 $
Total $
$70,000
$80,000
$70,000
$220,000
Title:
Target identification of chemical coded neural network for treating
obesity and its related metabolic disorders
Summary:
This project is about the study of central regulation of energy
balance contributing to prevention or development of chronic high-energy diet-induced
obesity. Obesity is a major predisposing factor for a variety of life threatening
diseases such as type II diabetes, hypertension, and coronary heart disease
with their enormous costs both socially and economically. Development of human
obesity and its related metabolic disorders generally develops over a long period
and eventually becomes a chronic condition. Generally, chronic consumption of
high-energy food in excess of expenditure leads to excessive fat accumulation
and promotes the development of obesity. However, under these conditions, some
individuals become obese, while others remain lean indicating that variation
in susceptibility is an important determinant of the development of obesity.
It is apparent that those individuals resistant to obesity have a more effective
defence system against excessive fat accumulation. Using the animal models developed
in our laboratory, the proposed research aims to search for the differences
in the central regulation between the mice resistant or susceptible to the development
of obesity. The outcomes we expect to achieve include: 1) better understanding
of central factors controlling energy balance, 2) clarification of the central
factors responsible for dysregulation of this system by chronic consumption
of a high-energy diet, and 3) identification of those factors contributing to
prevention against such dysregulation. Further, according to our previous study
[XFH1, 2, 3], we propose to use the drugs targeting on the specific receptor
subtypes to test reversibility of chronic high energy diet-induced obesity.
Chief Investigator(s):
Associate Professor John Carver, Professor Mark Walker
2002 $
2003 $
2004 $
Total $
$80,000
$80,000
$80,000
$240,000
Title:
Structure-function inter-relationships of small heat-shock chaperone
proteins
Summary:
In vivo, most proteins only function over a narrow temperature
or pH range. For example, if the solution containing a particular protein is
heated (stressed), the protein will unfold, aggregate and potentially precipitate.
The act of protein precipitation is an irreversible process that, in many cases,
has deleterious consequences for cell viability. Protein precipitation is associated
with a diversity of diseases, e.g. cataract and neurodegenerative diseases such
as Alzheimer's, Creutzfeldt-Jakob and Parkinson's diseases. Nature has evolved
cellular mechanisms to minimise protein misfolding, aggregation and precipitation
which principally utilise a diverse group of controlling or regulatory proteins
called molecular chaperones. Amongst the most important of these are the small
heat-shock proteins (sHsps) which are found in all organisms. sHsps function
by interacting in a very efficient manner with destabilised proteins to prevent
their precipitation. Little is known, however, about the structure of sHsps
nor the mechanism by which they perform their chaperone action. This proposal
will address these fundamental aspects via the use of a variety of spectroscopic
techniques, principally nuclear magnetic resonance (NMR) spectroscopy.
Chief Investigator(s):
Marie Ranson
2002 $
2003 $
Total $
$155,000
$235,000
$524,000
Title:
A new targeted therapy for cancer using alpha-PAI2
Summary:
Breast cancer is the most commonly diagnosed, malignant cancer
in women and prostate cancer is the most common non-life style related cancer
in men. In spite of the most aggressive therapy, a significant percentage of
men and women die of secondary disease (metastases) which usually spreads in
the early stages. Currently, therapy is limited to chemotherapy and hormone
therapy, both of which show clinical improvement but long term survival is uncertain.
Targeted alpha therapy (TAT) is a new cancer treatment that we are developing
in mouse models of human breast and prostate cancer. With TAT we are exploiting
the fact that aggressive breast and prostate cancer cells, but not normal cells,
express a particular tissue-barrier degrading protein system (uPA) which is
specifically recognised by a natural inhibitor protein (PAI2). This protein
inhibitor is labeled with a highly effective cell killing agent, a radioisotope
that emits high energy alpha particles with a short range of only a few cell
diameters . The alpha-labeled PAI2 selectively kills cancer cells at their most
malignant stage by targeting the uPA system on these cells. Another benefit
of TAT is that little radiation damage occurs to nearby or distant normal cells.
Thus side-effects would be minimised. The outcome of our research to date has
been to show the potential of our unique TAT approach as a possible new therapy
for breast and prostate cancer. This therapy may well prove beneficial for other
cancers. Further safety evaluations studies in mice will be followed by a dose
tolerance clinical trial in humans. We expect to be able to show that our TAT
will regress breast and prostate cancer tumours without complications in mice.
The human trials will show the tolerance limits to TAT. If successful, TAT could
provide the basis for a major change in prognosis and quality of life of breast
and prostate cancer patients.
