This application will investigate the potential for nanomaterials to have adverse effects on human health and to formulate approaches to screen nanomaterials for potential health risks, particularly those with a high likelihood for human exposure in Australia. Understanding how existing nanomaterials interact with biological systems will help determine the risk of adverse effects in the human population and identify those nanoparticles with little or no risk.
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
Effects Of Ageing On Hepatic Drug Clearance And Mechanisms Of Drug Induced Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
With increasing age, there is increase in disease, for which medications may provide benefit, and an increase in the risk of adverse drug reactions, even after considering the increase in medication use by older people. We will investigate how the liver clears drugs from the blood in old age. This will guide dosing of medications for older people. We will also study how drugs injure the liver in old age and test interventions to prevent this toxicity.
Elucidation Of The Molecular Requirements Of The Low Affinity 'state' Of The Beta1-adrenoceptor
Funder
National Health and Medical Research Council
Funding Amount
$535,500.00
Summary
Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to blo ....Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to block beta-receptors but they can also stimulate them at higher concentrations. Thus low concentrations block the effects of noradrenaline, but higher concentrations stimulate the receptor. More puzzling is that the stimulant effects of this group of beta-blockers cannot be easily blocked. To explain this we hypothesize that human beta-receptors can exist in two different 'states'. One 'state' can be stimulated by noradrenaline and blocked by low concentrations of beta-blockers such as propranolol and CGP 12177. Another 'state' of the same receptor is resistant to blockade by beta-blockers such as propranolol but can be stimulated by beta-blockers such as CGP 12177. This project seeks to investigate the molecular basis of the beta-adrenoceptor that is responsible for stimulant effects of beta-blockers. Specifically it explores the components of the beta-adrenoceptor that are critically and uniquely important for interacting with the stimulant beta-blockers. This project is an important increment in our laboratories research program to increase our understanding of the effects of beta-blockers. Our long term goal is to be able to develop beta-blockers that can block both states of the beta-adrenoceptor to provide a more effective block of the receptor and in particular for the improved management of heart failure.Read moreRead less
Molecular Determinants Of UDP Glucuronosyltransferase 1A3 And 1A4 Expression
Funder
National Health and Medical Research Council
Funding Amount
$516,078.00
Summary
Enzymes in the liver and gastrointestinal tract have a crucial role in protecting against the toxic effects of fat-soluble chemicals. Two of these enzymes called UGT1A3 and UGT1A4 have a special role in protecting against drugs and toxins that contain nitrogen groups. The levels of these two enzymes in the liver and gut vary extensively between individuals. In this project we will determine how the levels of these enzymes are controlled and what is the cause of this variability between individua ....Enzymes in the liver and gastrointestinal tract have a crucial role in protecting against the toxic effects of fat-soluble chemicals. Two of these enzymes called UGT1A3 and UGT1A4 have a special role in protecting against drugs and toxins that contain nitrogen groups. The levels of these two enzymes in the liver and gut vary extensively between individuals. In this project we will determine how the levels of these enzymes are controlled and what is the cause of this variability between individuals. This will help us predict those individuals who are more at risk from the adverse effects of nitrogen-containing drugs and from the toxic effects of chemicals in the diet or the environment. This project will also help us develop methods to increase the levels of these protective enzymes and help reduce the effects of exposure to toxic chemicals.Read moreRead less
Optimal Design Of Antimalarial Population Pharmacokinetic Studies
Funder
National Health and Medical Research Council
Funding Amount
$110,300.00
Summary
Each year there are more than 500 million episodes of malaria and over a million deaths. One of the main causes of this burden is inadequate treatment of young children and pregnant women. This project will improve research methods for determining effective treatment for all malaria patients, which in turn, will improve cure rates and slow the emergence and spread of drug resistance.
Our bodies generate a hormone called angiotensin II in response to a decrease in blood pressure (or salt in our bloodstream). This hormone increases blood pressure by causing blood vessels to constrict, by making us thirsty, and by inducing salt and fluid retention via an effect on the kidneys. In some cardiovascular diseases, the generation of angiotensin II or our sensitivity to this hormone is elevated. It is therefore crucial that we understand how angiotensin II works and how its actions in ....Our bodies generate a hormone called angiotensin II in response to a decrease in blood pressure (or salt in our bloodstream). This hormone increases blood pressure by causing blood vessels to constrict, by making us thirsty, and by inducing salt and fluid retention via an effect on the kidneys. In some cardiovascular diseases, the generation of angiotensin II or our sensitivity to this hormone is elevated. It is therefore crucial that we understand how angiotensin II works and how its actions in the body are mediated. For angiotensin II to act it must first bind to a receptor. Receptors are proteins and behave like locks that are opened by the hormone keys. Thus, cellular receptors for angiotensin II are engaged and activated by increases in angiotensin II in our blood. These receptors then produce signals which initiate a response (e.g. constriction of a blood vessel). Subsequently, the receptors are switched-off to prevent over-stimulation. The experiments proposed in this application continue our investigations into how angiotensin II receptors are regulated or switched-on and -off. A major way for receptors to be turned off is for them to be ear-marked by a modification known as phosphorylation. These modified receptors are then bound by proteins termed arrestins, which as indicated by their name play a role in preventing further receptor signalling. These arrestins also help remove activated receptors from the cell surface to the inside of the cell. How arrestins interact with receptors and regulate their function is poorly understood. This application proposes experiments to investigate the molecular mechanisms of arrestin action as it relates to the angiotensin II receptor. Results from these studies will further our understanding of angiotensin II receptors and their role in cardiovascular control.Read moreRead less
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