Function Of Sulfotransferase SULT4A1 - Transcriptional And Post-transcriptional Regulation
Funder
National Health and Medical Research Council
Funding Amount
$302,063.00
Summary
Our understanding of how important proteins work is critical to devising modern approaches for disease treatment. This project looks specifically at a protein sulfotransferase 4A1 linked with schizophrenia, and may be involved in other neuronal disorders. The plan is to characterise how the protein functions and what might be the implications of abnormal regulation. Through a series of intricate experiments, the molecular and cellular properties of the protein will be more clearly defined.
Molecular Mechanisms Of Human Cytochrome P450 CYP3A4 Gene Regulation
Funder
National Health and Medical Research Council
Funding Amount
$196,059.00
Summary
Liver cytochrome P450 enzymes are important to medicine in areas as broad as drug breakdown, steroid hormone regulation and the formation or elimination of cancer causing chemicals. These enzymes are present in high concentration in the human liver, but the factors governing how much of these enzymes are produced have been poorly understood. Cytochrome P450 3A4 (CYP3A4) is arguably the single most important factor is how humans handle therapeutic drugs. It has been estimated that over 60% of all ....Liver cytochrome P450 enzymes are important to medicine in areas as broad as drug breakdown, steroid hormone regulation and the formation or elimination of cancer causing chemicals. These enzymes are present in high concentration in the human liver, but the factors governing how much of these enzymes are produced have been poorly understood. Cytochrome P450 3A4 (CYP3A4) is arguably the single most important factor is how humans handle therapeutic drugs. It has been estimated that over 60% of all drugs presently on the market are broken down, either in full or in part, by this enzyme. The amounts of CYP3A4 expressed in the liver differs markedly between individuals, and explains a great deal of the large variation in the way people break down drugs. Also, variations in the levels of CYP3A4 in the liver may be an important factor in both prostate cancer (the most common cancer in men) and the risk of developing leukemia after receiving chemotherapy for other cancers. The present projects builds on discoveries concerning the regulation of cytochrome P450 enzymes made by our group over the last few years, including an in-depth understanding of the way the production of CYP3A4 is increased by some drugs. In this project we seek to understand why individuals differ so much in terms of the amount of CYP3A4 in the liver (up to 10-fold) and why this enzyme is predominantly expressed in the liver and to as lesser extent, the intestine, while not being found at all in many other tissues. An understanding of these issues will allow us to: Y predict how patients will respond to drugs (pharmacogenetic testing). Y determine susceptibility to certain diseases (e.g., prostate cancer). Y develop novel drugs that can influence CYP3A4 production in the liverRead moreRead less
Human Arylamine N-acetyltransferase Regulation And Function - Effect Of Genetic Poymorphisms.
Funder
National Health and Medical Research Council
Funding Amount
$421,980.00
Summary
How we handle chemicals that enter our bodies depends on a series of enzymes that are responsible for breaking down the chemicals and eliminating them. The activity of many of these enzymes varies between individuals so our responses to chemicals and drugs is different for each individual. Some of the enzymes vary because of inherited mutations, but others vary because of the diets we eat and the environment in which we live. This project will investigate a major enzyme called acetlytransferase ....How we handle chemicals that enter our bodies depends on a series of enzymes that are responsible for breaking down the chemicals and eliminating them. The activity of many of these enzymes varies between individuals so our responses to chemicals and drugs is different for each individual. Some of the enzymes vary because of inherited mutations, but others vary because of the diets we eat and the environment in which we live. This project will investigate a major enzyme called acetlytransferase that has been implicated as a risk factor in diseases such as cancer, asthma, liver cirrhossis and adverse drug reactions. We plan to look at the enzyme in cells and determine what environmental factors contribute to its variation between individuals, and how this impacts on the genetic mutations that have been found in its gene. From these studies, we will have a much better undersanding of how different people metabolise foreign chemicals, and should be able to predict those most at risk of certain diseases.Read moreRead less
I am a pharmacologist-cell biologist-molecular biologist and chemist examining the metabolism of iron in normal and neoplastic cells and the development of iron chelators for the treatment of a wide variety of diseases eg., ?-thalassaemia, cancer and Frie
Understanding The Pharmacoregulation Of The Extracellular Calcium Sensing Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$744,943.00
Summary
Calcium sensing receptors (CaSR) are important regulators of hormone release and modulators of kidney transport, digestion-absorption-satiety and bone mass. In each case, CaSRs adopt a characteristically distinct activating mechanism that we will unravel in detail sufficient for the development of novel chemotherapies e.g., for osteoporosis and obesity. We also anticipate early application of CaSR-based therapies to clinically significant genetic disorders e.g., neonatal hyperparathyroidism.
Astrocytic Glutamate Transporters: Molecular Characteristics Of Their Activity-dependent Localization And Targeting
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
Dysfunction of glutamate transport is implicated in the pathology of neurodegenerative conditions. Our aim is to understand how the molecules responsible for glutamate transport are organized on the cell surface and how their movement within cells regulates transporter activity. Advances of this type will indicate new pharmacological and molecular biological strategies for the management of brain disorders.
Understanding The Mechanisms Used By G-protein Coupled Receptors To Regulate Insulin-independent Glucose Transport
Funder
National Health and Medical Research Council
Funding Amount
$105,590.00
Summary
In type 2 diabetes, stimulation of glucose transport in fat cells and skeletal muscle by insulin is impaired. As a result there is great interest in identifying insulin-independent mechanisms that increase glucose transport. Several G-protein coupled receptors (GPCRs) regulate glucose transport independently of insulin but the mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate glucose transport for potential as treatments.
Cytochrome P450 CYP3A Regulation In Humanized Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$376,980.00
Summary
The study of the regulation of human genes is inherently difficult. It is difficult or impossible to gain access to many body tissues in either healthy or sick individuals to examine coordinated gene function (or dysfunction). For this reason, it is often the case that we have a much better understanding of gene function in species such as rats and mice, the most common animal environments for biomedical research. However, findings in animals often fail to meaningfully mirror what occurs in man. ....The study of the regulation of human genes is inherently difficult. It is difficult or impossible to gain access to many body tissues in either healthy or sick individuals to examine coordinated gene function (or dysfunction). For this reason, it is often the case that we have a much better understanding of gene function in species such as rats and mice, the most common animal environments for biomedical research. However, findings in animals often fail to meaningfully mirror what occurs in man. To progress our understanding of human genes we need to develop models that more faithfully reproduce the human situation in an environment that is amenable to both manipulation and close examination, such as the novel 'humanised' mouse models described in this application. This application deals with the regulation genes that control liver enzymes belonging to the human cytochrome P450 3A (CYP3A) subfamily. These enzymes are present in several tissues including liver, gut, lung and breast. They form the main disposal pathway for foreign chemicals such as drugs, environmental pollutants and some cancer causing chemicals. In addition they are involved in the breakdown of several important internally produced substances, such as steroid hormones. Altered formation of CYP3A enzymes can have a dramatic impact on the action of many important drugs and may predispose to some forms of cancer. In this project, we will insert the genes for all four human CYP3A enzymes into mice. We expect that these 'humanised' mouse models will effectively enable the human situation to be studied in a convenient animal model and allow detailed studies to be performed. A knowledge of the mechanisms involved in CYP3A enzyme formation is of particular importance to the fields of drug and steroid metabolism (both in health and in disease states), liver diseases and foetal pharmacology. In addition, these models will provide a new and useful tool for drug development.Read moreRead less
Molecular Mechanism And Novel Activators Of Amino Acid And Calcium-sensing Class 3 G-protein Coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
When we eat protein-containing foods, our bodies extract twenty different amino acids for growth and tissue regeneration. Broad-spectrum amino acid sensing receptors detect the increases in blood amino acid levels and respond by triggering the release of biochemical signals. This project will establish the molecular rules by which these receptors work and identify novel activators with potential therapeutic application for the control of growth, tissue regeneration and calcium metabolism.