Old age is the main risk factor for atherosclerosis, which is the main cause of mortality and morbidity in the World. We found age-related changes in the microcirculation of the liver called pseudocapillarization that provide a mechanism linking old age with atherosclerosis. Pores in the endothelium called fenestrations disappear, impairing the ability of the liver to breakdown fats. New therapies to treat and prevent age-related pseudocapillarization are being developed.
Pharmacological Targeting Of Arylamine N-Acetyltransferase I
Funder
National Health and Medical Research Council
Funding Amount
$474,653.00
Summary
This project will investigate a novel approach to controlling how cancer cells grow and spread. It plans to study whether a protein termed N-acetyltransferase is a key to determining whether cancer cells can change thier characteristics, allowing them to invade other tissues. In addition, novel approaches to target this protein are proposed. If successful, the work outlined in this project will open new avenues to understanding and trerating cancers.
Pharmacological Targeting Via AKT, PTEN, And TGF-beta Pathway Integration Using Novel Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$634,875.00
Summary
We have identified potentially important interactions of cellular pathways that vary between individual sufferers, but which also provide common molecular targets for novel drug development. Our suite of novel and potent drugs that markedly and selectively inhibit cancer cell growth will be studied to determine if these pharmaceutical agents act to inhibit tumour cell proliferation by targeting common effector molecules of integrated cellular pathways.
UDP Glucuronosyltransferases As Regulators Of Signaling Pathways Modulated By Chemical Ligands.
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
Cells respond to their surroundings by transferring information received at the cell surface to the nucleus leading to changes in gene expression. There are many signaling pathways which transfer this informatrion to the nucleus. Some of these pathways are controlled by small molecules, usually fat-soluble chemicals. As a family of enzymes, the UDP glucuronosyltransferases (UGT) have evolved to eliminate fat-soluble chemicals, we propose that UGTs play a pivotal role in regulating the concentrat ....Cells respond to their surroundings by transferring information received at the cell surface to the nucleus leading to changes in gene expression. There are many signaling pathways which transfer this informatrion to the nucleus. Some of these pathways are controlled by small molecules, usually fat-soluble chemicals. As a family of enzymes, the UDP glucuronosyltransferases (UGT) have evolved to eliminate fat-soluble chemicals, we propose that UGTs play a pivotal role in regulating the concentrations of fat-soluble chemicals involved in signaling, and thus are important in controlling gene expression. We intend to provide evidence for this novel role of UGTs in this project. This information will be used to alter the response of the cell to its environment. For example, to help protect the cell against environmental toxins, or to make a cancer cell more susceptible to a chemotherapeutic agent.Read moreRead less
The Mechanism Of Action Of New 5-nitroimidazole Drugs Which Are Effective Against Metronidazole-resistant Giardia
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
We have discovered new 5-nitroimidazole drugs which can overcome giardial resistance to metronidazole, the most prescribed 5-nitroimidazole drug to treat giardiasis. We will focus on defining mechanisms of action of these new 5-nitroimidazole drugs in the anaerobic gut protozoan parasite Giardia. Using biochemical techniques, we will determine whether our potent new drugs are activated more efficiently by the same mechanisms as metronidazole or by novel enzyme pathways in the parasite.
Probing UDP-glucuronosyltransferase Protein-protein Interactions: The Power Of Two.
Funder
National Health and Medical Research Council
Funding Amount
$482,710.00
Summary
Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransfera ....Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransferase (UGT) is one of the most important enzymes involved in drug and chemical metabolism. Consistent with its ability to metabolise such a large number of compounds, UGT is known to exist as a 'superfamily' of structurally related proteins. Despite the importance of UGT, little is known about the structural characteristics of these enzymes that are responsible for recognising and binding different classes of chemicals. Accumulating evidence from this and other laboratories indicates that the individual UGT proteins may combine with themselves (to form a homodimer) and with other UGT proteins (to form heterodimers). This project largely seeks to define the scope of UGT homo- and hetero- dimerisation, identify the structural elements of the proteins responsible for association and characterise the functional significance of dimerisation. The project will further explore associations between UGTs and other proteins, namely albumin. Characterisation of UGT dimerisation and associations with other proteins is fundamental to our understanding of how this enzyme functions and selects particular chemicals for metabolism. The work also has important implications for the devlopment and interpretation of in vitro (or 'test-tube') approaches for predicting how drugs are metabolised in humans. Such tests are widely employed in research and pharmaceutical company laboratories to predict how the body 'handles' new drugs prior to their administration to humans.Read moreRead less
Investigation Of A Tumour Enzyme As A Predictor Of Patient Response To An Australian Anti-cancer Drug
Funder
National Health and Medical Research Council
Funding Amount
$362,082.00
Summary
GSAO is a new cancer drug we have developed that is currently being trialed in cancer patients. Our investigation of how GSAO works has revealed that it needs to be activated by an enzyme expressed by certain types of cancers. This finding implies that GSAO should be more effective against cancers that make this enzyme. Our aim is to establish this concept in laboratory based experiments as a basis for selection of patients who are more likely to benefit from GSAO treatment.
Evaluating The Potential Of HERG Channel Agonists As Mechanistically Targeted Antiarrhythmics
Funder
National Health and Medical Research Council
Funding Amount
$414,786.00
Summary
Abnormal heart rhythms cause ~10 % of deaths in the western world and this number is increasing. To date there has been little success in identifying drugs that are effective in treating these disorders. By studying a rhythm disturbance called long QT syndrome we will examine whether specifically targeting drugs to the molecular building blocks of these arrhythmias is an appropriate route for development of more effective drugs.
Design, Development And Analysis Of New Tuberculosis Drugs
Funder
National Health and Medical Research Council
Funding Amount
$736,628.00
Summary
Serious issues of drug resistance have emerged in tuberculosis prevention and are placing enormous pressure on global health systems. We have identified an enzyme of M. tuberculosis that is essential for its survival. This project will develop potent inhibitory compounds for this enzyme. Further, we will identify new drug targets through a screen to specifically identify the genes of the organism essential for its survival in the body. This information will be used to develop new TB drugs.
Development Of Anti-tropomyosin Drugs For The Treatment Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$578,352.00
Summary
Australia has the highest incidence of melanoma worldwide. There is a clear need to develop new strategies as melanoma is unresponsive to current treatment regimes. We have developed a compound, TR100, which targets a specific component of the cytoskeleton of melanoma tumour cells. Disruption of this cytoskeleton leads to decreased tumour cell growth and survival. Understanding the mechanism by which TR100 causes cell death is important if this novel anti-cancer compound is to be used in the cli ....Australia has the highest incidence of melanoma worldwide. There is a clear need to develop new strategies as melanoma is unresponsive to current treatment regimes. We have developed a compound, TR100, which targets a specific component of the cytoskeleton of melanoma tumour cells. Disruption of this cytoskeleton leads to decreased tumour cell growth and survival. Understanding the mechanism by which TR100 causes cell death is important if this novel anti-cancer compound is to be used in the clinic.Read moreRead less