Activation Mechanisms Of The Hypoxia Inducible Factor-1a (HIF-1a) And The HIF-Like-Factor
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
A continual supply of oxygen is essential for normal functioning of the human body. When oxygen levels become limiting, the body attempts to rectify the situation by increasing the number of oxygen carrying red blood cells and promoting development of new blood vessels to increase the blood supply to tissues. Cells also adapt by altering their internal biochemistry and metabolism to decrease energy needs. These changes are the result of a genetic reprogramming within the cells. A major question ....A continual supply of oxygen is essential for normal functioning of the human body. When oxygen levels become limiting, the body attempts to rectify the situation by increasing the number of oxygen carrying red blood cells and promoting development of new blood vessels to increase the blood supply to tissues. Cells also adapt by altering their internal biochemistry and metabolism to decrease energy needs. These changes are the result of a genetic reprogramming within the cells. A major question is how the cells sense they are in a low oxygen environment and by what mechanisms they initiate genetic reprogramming. We are studying two proteins which have the ability to alter activity of genes when cells are stressed by hypoxia (low oxygen), and seek to discover how the proteins switch from latent forms to active forms in response to hypoxia. A greater understanding of the molecular mechanisms involved in the cellular hypoxic response is important to the development of new therapeutics for disease states involving disrupted oxygen flow (eg heart attack and stroke). Drugs which would block the hypoxic induced development of blood vessels could also be extremely beneficial in cancer treatment, as blocking blood supply to growing tumours can result in their starvation and shrinkage.Read moreRead less
Roles Of Chaperone Proteins And Phosphorylation Events In Activity Of The Dioxin Receptor
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
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
Understanding Transcription Factor Interactions In Blood Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
All blood cells develop from the same parent cells, which are known as stem cells. Once the decision is made for a stem cell to develop into a particular type of blood cell, mechanisms must exist that ensure the cell only expresses the genes that are appropriate for that cell type. These mechanisms involve the action of proteins known as transcription factors, which specifically activate the expression of the correct genes. While deregulation of these control mechanisms often leads to diseases s ....All blood cells develop from the same parent cells, which are known as stem cells. Once the decision is made for a stem cell to develop into a particular type of blood cell, mechanisms must exist that ensure the cell only expresses the genes that are appropriate for that cell type. These mechanisms involve the action of proteins known as transcription factors, which specifically activate the expression of the correct genes. While deregulation of these control mechanisms often leads to diseases such as cancer, unfortunately our understanding of how networks of transcription factors combine to direct processes such as blood cell development is relatively poor. GATA-1 and PU.1 are essential for the normal development of erythroid and myeloid blood cell types, respectively, and the work in the present proposal is aimed at understanding some of the molecular details of how direct interactions between these two proteins modulate their activity. This information should prove useful in understanding other transcriptionally regulated systems and may eventually help provide a route to treating a number of classes of blood cancer.Read moreRead less
I am a structural biologist with a background in pharmacy. My research focuses on dissecting the molecular mechanisms of disease-causing proteins to underpin the development of new and improved therapeutics
Biological Role And Partners Of The LIM Domain Protein LMO4 In Breast Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$120,181.00
Summary
Breast cancer is the most common cancer affecting women, with 1 in 14 developing this disease. Although treatment of breast cancer has substantially improved over the last few years, 30% of women diagnosed with this cancer will die from it. One major focus of cancer research is the identification of genes involved in tumour development and definition of their precise role in cancer cells. The design of effective therapeutic inhibitors of cancer requires an understanding of the basic molecular an ....Breast cancer is the most common cancer affecting women, with 1 in 14 developing this disease. Although treatment of breast cancer has substantially improved over the last few years, 30% of women diagnosed with this cancer will die from it. One major focus of cancer research is the identification of genes involved in tumour development and definition of their precise role in cancer cells. The design of effective therapeutic inhibitors of cancer requires an understanding of the basic molecular and cellular biology behind the genetic changes thought to contribute to cancer. The focus of our research is to understand normal cellular mechanisms that drive growth and differentiation of breast tissue, and those changes that lead to breast cancer. Nuclear regulatory proteins have been implicated in many different types of cancers and leukaemias. We aim to identify the key regulators in breast tissue, characterising both their structural properties and biological roles, with the ultimate view of understanding how they divert a normal cell to a cancerous cell.Read moreRead less
Erythroid Molecular Cascades Involving The Tyrosine Kinase Lyn
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Mature red and white cells develope from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (Epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for Epo to stimulate them to become mature functio ....Mature red and white cells develope from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (Epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for Epo to stimulate them to become mature functional cells. Recently, we have demonstrated that mice lacking the Lyn gene develope major problems with their red blood cells. We have identified several molecules which interact with Lyn in red blood cells. We have shown that a molecule called Cbp is important for Epo function in individual red blood cells and now we plan to investigate its function in whole animals. We have shown that a new molecule called Arp is important for red blood cell development. This protein moves in and out of the nucleus (where DNA is stored) and may be important in the regulation of genes needed for red blood cells. The third gene (AFAPbeta) is also novel and is closely related to another called AFAP-110, which can exert effects on the structure of a cell. Since red blood cells have to shrink considerably during their development, the role of AFAPbeta on red blood cell structure will also be investigated. From these experiments we should develop a much better understanding of how the production of red blood cells is controlled and how diseases of red blood cells (such as anaemia) occur.Read moreRead less
Roles Of Integrin Receptors And The Helicobacter Pylori Protein CagL In Gastritis And Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$290,697.00
Summary
How the bacterium Helicobacter pylori (Hp) causes gastritis and gastric cancer in the stomach is not well understood. Here we investigate the molecular languages used by Hp to deregulate the normal functions of the human stomach cells. The research outcomes will on one hand help us to better understand how Hp causes diseases, and on the other hand, facilitate the development of new antibiotics or treatment therapies to combat gastric cancers and gastritis.