Alternate Signalling Pathways Regulating The Human Arachidonate Epoxygenase CYP2J2 In Response To Stress Stimuli
Funder
National Health and Medical Research Council
Funding Amount
$369,000.00
Summary
Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid ....Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid products inside cells, is decreased in hypoxia and that this is due to increased activity of AP-1. We know that similar stressful stimuli can also result in a loss of CYP2J2. Again, AP-1 is involved but we have further evidence for the role of another pathway. This project will explore how these pathways operate individually and together to decrease CYP2J2. Studying the regulation of human genes is difficult because we can not readily monitor their levels in cells in either healthy or sick individuals. So we will make transgenic mouse models to study human CYP2J2 regulation, which will provide information on the human situation. In this project we will identify which factors switch off the CYP2J2 transgene and will analyse the signalling pathways within cells that control this response. The importance of these studies is that they will help us to design pharmacological strategies to prevent the loss of CYP2J2 in cells that are stressed. Such agents may be effective in the treatment of ischaemic injury seen in stroke and atherosclerosis. If we can maintain CYP2J2 levels we may be able to maintain the beneficial fatty acid levels in cells and have a novel therapeutic approach for keeping cells alive.Read moreRead less
The Roles Of Lipoprotein Multigene Families In Pathogenesis Of Mycoplasma Pneumoniae
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Mycoplasma pneumoniae is one of the most common causes of community acquired pneumonia. Although it can usually be successfully treated with antibiotics, it can result in more severe diseases and can be difficult to diagnose accurately. It has been identified as a target for vaccine development, but this has been hampered by the limited understanding we have of how it causes disease. The attempts at vaccination that have been made have resulted in vaccines which induced more severe, rather than ....Mycoplasma pneumoniae is one of the most common causes of community acquired pneumonia. Although it can usually be successfully treated with antibiotics, it can result in more severe diseases and can be difficult to diagnose accurately. It has been identified as a target for vaccine development, but this has been hampered by the limited understanding we have of how it causes disease. The attempts at vaccination that have been made have resulted in vaccines which induced more severe, rather than less severe, disease. Investigations of several other related bacteria have shown that they are able to vary their surface proteins and thus may evade the immune system, permitting them to cause more prolonged disease. Better understanding how this occurs, and what this enables the bacteria to do, may assist in developing improved vaccine strategies. This project aims to investigate the six gene families in Mycoplasma pneumoniae which are known to encode surface proteins and establish how and why the bacteria switch from one gene to another during infection. In addition the capacity of bacteria expressing different versions of the six surface proteins to adhere to different tissues will be investigated. Once this is known, these mechanisms may be able to be specifically disrupted to prevent a strain of Mycoplasma pneumoniae from being able to establish prolonged infections. Such a strain might be a useful basis for an effective vaccine.Read moreRead less
Importance Of The Brain Renin-Angiotensin System For Regulating Blood Pressure And Cardiovascular Autonomic Function.
Funder
National Health and Medical Research Council
Funding Amount
$609,424.00
Summary
The peptide angiotensin a major regulator of many brain areas controlling blood volume and blood pressure. Brain angiotensin may well contribute to high blood pressure but how it acts in each of the different brain areas is unknown. New gene transfer technology using viruses combined with genetically modified mice will enable this project to inactivate or activate angiotensin in each brain nucleus and determine the role of individual areas to setting of blood pressure leading to hypertension.
Mechanism/s Of Disease Caused By Respiratory Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$479,517.00
Summary
A newly discovered respiratory virus, human metapneumovirus (HMPV), causes clinical disease that is very similar to human respiratory syncytial virus (RSV) and co-circulates with RSV. Human RSV is a major cause of morbidity and life-threatening respiratory tract disease in infants and young children worldwide, and is recognised as an important respiratory pathogen in elderly adults and immune compromised patients. The recent isolation of HMPV from children hospitalised with respiratory tract ill ....A newly discovered respiratory virus, human metapneumovirus (HMPV), causes clinical disease that is very similar to human respiratory syncytial virus (RSV) and co-circulates with RSV. Human RSV is a major cause of morbidity and life-threatening respiratory tract disease in infants and young children worldwide, and is recognised as an important respiratory pathogen in elderly adults and immune compromised patients. The recent isolation of HMPV from children hospitalised with respiratory tract illness similar to RSV, but with an unknown etiology, suggests that HMPV may mediate similar clinical pathology. Nothing is currently known about the immune response to HMPV, or the association of these responses with lung disease. The objectives of this proposal are to elucidate the mechanisms of immunity and disease pathogenesis associated with human metapneumovirus (HMPV) and to investigate the use of a novel vaccine to protect against HMPV infection. Once this data is obtained, the study will provide the foundation for further research in the development of vaccines or therapeutic protocols to treat HMPV. It will also provide valuable information for understanding the disease in humans. Also,it is likely that HMPV, like hRSV, may prove to be an agent associated with long-term decreased pulmonary function and airflow limitation perhaps developing to asthma.Read moreRead less