HYPOXIA AND THE TRANSCRIPTIONAL REGULATION OF CYP GENES IN CELLS
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Hypoxia, or oxygen deprivation caused by the decreased supply of blood to cells, is a component of ischaemic injury of the cardiovascular system (as in angina or atherosclerosis) and numerous other organs (e.g. in cancer and chemical-mediated injury). It is now known that the content of certain proteins that activate specialised target genes is increased rapidly in cells in response to oxygen deprivation. Some of the most important of these proteins are hypoxia-inducible factor-1 (or HIF-1) and ....Hypoxia, or oxygen deprivation caused by the decreased supply of blood to cells, is a component of ischaemic injury of the cardiovascular system (as in angina or atherosclerosis) and numerous other organs (e.g. in cancer and chemical-mediated injury). It is now known that the content of certain proteins that activate specialised target genes is increased rapidly in cells in response to oxygen deprivation. Some of the most important of these proteins are hypoxia-inducible factor-1 (or HIF-1) and activator protein-1 (or AP-1). We have identified a novel target gene that is activated in hypoxia. This gene produces an enzyme, termed cytochrome P450 2J2, that acts on fatty acids which are present in cell membranes and converts them into molecules that control the flow of potassium and calcium ions into cells. Alterations in the flow of such ions into cells have been observed previously in hypoxia but the mechanism of this effect is unclear. Thus, cytochrome P450 2J2 is switched on in hypoxia and generates fatty acid metabolites that control protective ion fluxes in cells.Read moreRead less
Roles For Gastrin And Hypoxia In Colorectal Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$636,508.00
Summary
Our objective is to understand how hormones such as gastrin stimulate the development of colorectal cancer. Our preliminary data shows that the amount of gastrin produced by tumour cells is increased by low oxygen. We will therefore study how the increase in gastrin in response to low oxygen causes a compensatory growth of the tumour. The ability to interfere with this process should allow us to slow tumour growth.
Novel Tools For The Imaging Of Tumor Hypoxia Using PET
Funder
National Health and Medical Research Council
Funding Amount
$727,856.00
Summary
Fast growing tumors often outgrow the ability of blood vessels to properly supply them with nutrients and oxygen. This creates tissue areas within the tumor that are lacking oxygen and are highly resistant to radiotherapy and chemotherapy. Imaging these areas using nuclear medicine techniques has now become important for therapy planning of cancer sufferers. This project aims to improve the properties of the existing agents in order to better select patients for a particular type of treatment.
GABA Excitotoxicity, Neuroprotection And The Perinatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Approximately 3.5% of babies die each year from brain damage due to perinatal asphyxia, a shortage of oxygen to the developing brain. Babies that survive face lifelong neurological disabilities, placing enormous burden on health, social and economic resources. Current treatments are inadequate. We will examine what occurs when there is a shortage of oxygen to the developing brain and investigate pathways to hypoxic brain injury that offer opportunities for therapeutic intervention.
Novel Anti-Infective Agents That Act By Enhancing The Host Innate Response
Funder
National Health and Medical Research Council
Funding Amount
$655,482.00
Summary
Antibiotic resistance is one of our major challenges, with fears expressed that we may soon run out of effective antibiotics for the treatment of infections. The goal of this project is to develop a novel class of antibiotics that acts by enhancing our immune response to infection rather than attacking the bacteria themselves, and therefore will not be susceptible to the development of bacterial resistance. These agents inhibit the degradation of a key enzyme involved in combating infections.
Control Of Influenza A Virus Infection By Gamma Interferon-inducible Mediators
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Influenza A virus is a cause of morbidity and mortality worldwide. Due to antigenic shift and drift of the virus, including the emergence of pandemic strains, humans are often challenged with strains different from those to which they have been exposed by vaccination or prior infection. This has historically resulted in very serious increases in illness and death. The most severe pandemic of influenza A virus that has occurred in modern times was the worldwide pandemic of 1918-1920 when over 20 ....Influenza A virus is a cause of morbidity and mortality worldwide. Due to antigenic shift and drift of the virus, including the emergence of pandemic strains, humans are often challenged with strains different from those to which they have been exposed by vaccination or prior infection. This has historically resulted in very serious increases in illness and death. The most severe pandemic of influenza A virus that has occurred in modern times was the worldwide pandemic of 1918-1920 when over 20 million deaths occurred. Development of new interventive strategies to combat virus-related illness therefore remains critical to complement the present vaccine approach. For this, a clear understanding of the host's response to influenza virus infection is essential. For its part, the immune system has at its disposal several strategies to combat influenza A virus. How the immune system deals with the virus is controlled by a complex network of interactions involving cells, cell surface molecules, soluble mediators termed cytokines and chemokines. One cytokine, interferon-gamma, seems to be a key player in the body s ability to get rid of the virus. Here, we are trying to understand how interferon-gamma does this. We believe that this cytokine causes specific immune cells to produce other molecules, such as indolamine 2,3-deoxygenase (IDO) and chemokines, and that it is these molecules that control virus growth. We do not know whether these molecules stop virus growth directly or by creating the right conditions for this. We are interested in understanding the sequence of events that is started by interferon-gamma and ends in the clearance of virus from the lungs. To study the immune response to influenza virus, we use a mouse model that reproduces most features of the human disease. By understanding the events that lead to effective virus clearance in this disease, it may be possible to design new ways in which to combat this problematic infection in humans.Read moreRead less