Deciphering Posttranslational Codes Of The Dioxin Receptor
Funder
National Health and Medical Research Council
Funding Amount
$540,083.00
Summary
The dioxin receptor (DR) is a protein which protects human cells by binding xenobiotics, ie foreign or anti-nutritional chemicals found in food sources and the general environment. When these chemicals bind the DR, it becomes an active gene regulatory protein, turning on genes that are involved in breakdown and excretion of the xenobiotics. Recently it has been found that the DR performs other important functions which are unrelated to xenobiotic breakdown. These include blood vessel development ....The dioxin receptor (DR) is a protein which protects human cells by binding xenobiotics, ie foreign or anti-nutritional chemicals found in food sources and the general environment. When these chemicals bind the DR, it becomes an active gene regulatory protein, turning on genes that are involved in breakdown and excretion of the xenobiotics. Recently it has been found that the DR performs other important functions which are unrelated to xenobiotic breakdown. These include blood vessel development in the embryonic liver and hormone production during the estrous cycle. These observations imply that natural physiological mechanisms also exist for activating the DR, providing it with a separate code to perform these innate functions. A number of man-made chemicals, such as dioxins and PCBs, are especially good at activating the DR. However, they have chlorinated chemical structures, which are not broken down by the protective system. This creates a wide range of severe toxic responses. It has been established that toxicities result from persistent hyperactivation of the DR, but how this hyperactivation induces the toxic outcomes is not known. As the DR has roles in early development and estrogen production, this project will investigate how the DR becomes activated to perform these functions. Our initial experiments have shown that the DR can be activated by normal cell signalling systems, which induce distinct modifications (a distinct code) to the protein. We are comparing this code of modifications to those induced by xenobiotics which are able to be broken down, and dioxins which are resistant to breakdown. We hypothesise that dioxins will give an excessive code of activating modifications, resulting in uncontrolled regulation of genes used in both the developmental and xenobiotic breakdown pathways. We will explore the hypothesis that this gross loss of gene regulatory control underpins the multifarious toxicities of dioxin poisoning.Read moreRead less
I am interested in determining the molecular basis of immune recognition of foreign and self-antigens in the context of viral, tumor and auto-immunity as well as transplantation. In addition to fundamental observations this knowledge is also applied in va
Identification And Function Of Posttranslational Modifications In The Dioxin Receptor/Arnt Transcription Factor
Funder
National Health and Medical Research Council
Funding Amount
$448,500.00
Summary
Polycyclic aromatic hydrocarbons (PAHs) are prevalent environmental pollutants which cause a wide range of deleterious health effects. Metabolic activation of PAHs occurs primarily through a set of intracellular oxidising enzymes which are induced by the presence of PAHs. The dioxin receptor is a gene regulatory protein that is pivotal in the metabolic pathway as it links the presence of contaminating PAHs to induction of the enzymes responsible for initiating their metabolism. While in many cas ....Polycyclic aromatic hydrocarbons (PAHs) are prevalent environmental pollutants which cause a wide range of deleterious health effects. Metabolic activation of PAHs occurs primarily through a set of intracellular oxidising enzymes which are induced by the presence of PAHs. The dioxin receptor is a gene regulatory protein that is pivotal in the metabolic pathway as it links the presence of contaminating PAHs to induction of the enzymes responsible for initiating their metabolism. While in many cases PAHs are oxidised to compounds which are water soluble and excretable (and therefore harmless), some substrates, such as benzo[a]pyrene found in cigarette smoke, can become inadvertently transformed into carcinogens. Other pollutants such as dioxin are resistant to metabolism and are extremely toxic. We have an ongoing interest in deciphering the biochemical pathways which lead to aberrant metabolism, and as such are studying the mechanistic role of the dioxin receptor in this process.Read moreRead less
Analysis Of The C-terminal Hypervariable Region Of Ras Proteins
Funder
National Health and Medical Research Council
Funding Amount
$419,241.00
Summary
In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates one major signaling pathway, is mutated in 90% of pancreatic cancers, 50% of colon cancers and 30% of acute leukaemias. This leaves Ras and the signaling pathway permanently switched on causing uncontrolled cell proliferation. The clinical impact of drugs that could neutrali ....In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates one major signaling pathway, is mutated in 90% of pancreatic cancers, 50% of colon cancers and 30% of acute leukaemias. This leaves Ras and the signaling pathway permanently switched on causing uncontrolled cell proliferation. The clinical impact of drugs that could neutralise Ras function in these tumours is potentially enormous. Our previous work demonstrated that Ras must be attached to the inner surface of the cell membrane in order to function properly. This project now seeks to understand exactly how Ras gets to and attaches to the cell membrane. Once we understand this mechanism drugs can be designed to block Ras getting to the membrane. Such drugs should neutralize the effect of Ras in tumours and control cell proliferation. In fact, our previous study has already led to the identification of the first generation of anti-Ras drugs that work on this principle.Read moreRead less
Molecular Identification Of Causative Genetic And Epigenetic Alterations That Induce And Promote Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$381,821.00
Summary
The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that under ....The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that underpin the probable cause of colon cancer. We therefore propose to genetically engineer unique mouse models that focus on colon cancer to most closely replicate the situation in human disease. These models will then be available to others and us to develop and test therapies to prevent and-or treat colorectal cancer that will ultimately be used in patients.Read moreRead less