Role Of Placental Heme-oxygenase Pathway In Regulating Preterm Neonatal Cardiovascular Function
Funder
National Health and Medical Research Council
Funding Amount
$176,719.00
Summary
Babies born prematurely are more likely to experience problems as a result of being born early with males doing worse than females. The mechanisms causing this difference are unknown. The control of blood flow in the placenta and fetus is essential for normal growth and development. This project will investigate the influence of duration of pregnancy, gender, and exposure to antenatal steroids on pathways that control blood flow in the placenta and the newborn in babies born after prematurely.
THE REGULATORY MECHANISM OF HAEM OXYGENASE PROTECTION AGAINST PHOTOIMMUNOSUPPRESSION AND SKIN CANCER
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
Current dogma holds that UVA radiation adds to UVB damage in the skin. However we have identified a window of UVA doses, easily achievable from daytime sunlight exposure, that do not cause sunburn and are not immunosuppressive, but that significantly attenuate the damaging effects of UVB. In mice the mechanism partially depends on the UVA-upregulated cytokine interferon-gamma, and strongly on the UVA-inducible antioxidant enzyme haem oxygenase-1 (HO-1). This project aims to establish how the HO- ....Current dogma holds that UVA radiation adds to UVB damage in the skin. However we have identified a window of UVA doses, easily achievable from daytime sunlight exposure, that do not cause sunburn and are not immunosuppressive, but that significantly attenuate the damaging effects of UVB. In mice the mechanism partially depends on the UVA-upregulated cytokine interferon-gamma, and strongly on the UVA-inducible antioxidant enzyme haem oxygenase-1 (HO-1). This project aims to establish how the HO-1 gene is regulated by UVA. Available data from cultured human skin cells suggest that HO-1 is UVA-inducible in fibroblasts but not keratinocytes, whereas we found both cell types respond in mouse skin, keratinocytes most actively. We will ascertain whether a species difference, or an anomaly in cultured cells, underlies these discrepancies. With human skin grafted onto immunodeficient SCID mice, we will study impaired immune function, an important prerequisite for cancer, compared with mouse skin in vivo. Using molecular biology techniques with this model, we will monitor the activity of the transcription factor Bach 1, known to bind to the DNA of the HO-1 promoter region to repress the gene normally, but reversibly by haem-binding, and the corresponding activity of HO-1, during immunoprotective (UVA exposure, haem elevated) conditions. Immunoprotection may result from binding by Bach 1 of haem released from microsomal proteins by UVA, its release from DNA and thus derepression of HO-1. We will seek evidence of a role for skin cytokines in modifying Bach 1 binding, and for Bach 1 and HO-1 actions during photocarcinogenesis induction with chronic UV exposure. The significance of the outcome of the studies will be in understanding how a natural ameliorating pathway induced by UVA radiation could be utilised for superior photoprotection strategies for skin cancer susceptible humans.Read moreRead less
Metabolism And Neurotoxicity Of Hemin And Hemin-derived Iron
Funder
National Health and Medical Research Council
Funding Amount
$346,400.00
Summary
Stroke is a leading cause of death and disability in industrialised countries. Much of the brain damage that follows a hemorrhagic stroke is attributable to the presence of free iron which mediates oxidative stress in brain cells. This iron originates from hemin, which in turn is derived from the hemoglobin in extravasated blood cells. The fact that iron is freed from hemin in the post-stroke period makes it an attractive therapeutic target. However, remarkably little is known about the metaboli ....Stroke is a leading cause of death and disability in industrialised countries. Much of the brain damage that follows a hemorrhagic stroke is attributable to the presence of free iron which mediates oxidative stress in brain cells. This iron originates from hemin, which in turn is derived from the hemoglobin in extravasated blood cells. The fact that iron is freed from hemin in the post-stroke period makes it an attractive therapeutic target. However, remarkably little is known about the metabolism of hemin by the different types of brain cells. The present project investigates the metabolism and neurotoxicity of hemin in brain cells and will examine the capacity of potential therapeutic agents to protect brain cells from hemin toxicity. The data obtained from this project will advance our understanding of the uptake and metabolism of hemin by the four main types of brain cell, and the factors that are likely to be involved in the neurotoxicity of hemin-derived iron following hemorrhagic stroke. The study will also provide data concerning the relative effectiveness of potential therapeutic agents, and information concerning the cell types, time points and aspects of hemin metabolism that are most effectively targeted by these agents. Such advances will guide the development of therapeutic approaches that are directed at minimising the brain damage which results from hemin-derived iron in humans.Read moreRead less
COX-2 INHIBITORS AS A CAUSE OF HEART AND RENAL FAILURE
Funder
National Health and Medical Research Council
Funding Amount
$271,610.00
Summary
Non-steroid anti-inflammatory drugs (NSAIDs) have pain-killing and anti-inflammatory properties. For many years Australia had a higher use of these drugs than other countries. The drugs are quite toxic, and in susceptible individuals may cause ulceration and bleeding from the stomach and duodenum, kidney damage and fluid congestion leading to heart failure. Each of these conditions carries a high morbidity, particularly in the elderly. Because of concerns about toxicity, the use of NSAIDs in Aus ....Non-steroid anti-inflammatory drugs (NSAIDs) have pain-killing and anti-inflammatory properties. For many years Australia had a higher use of these drugs than other countries. The drugs are quite toxic, and in susceptible individuals may cause ulceration and bleeding from the stomach and duodenum, kidney damage and fluid congestion leading to heart failure. Each of these conditions carries a high morbidity, particularly in the elderly. Because of concerns about toxicity, the use of NSAIDs in Australia fell during the 1990s by around 40%. Newer allegedly safer forms of NSAIDs called COX-2 inhibitors have been introduced into the Australian market. The first 2 drugs to be marketed are called Celebrex and Vioxx. These drugs appear to be safer for the stomach and duodenum, but the true effects on the kidney and heart are as yet unclear. COX-2 inhibitors have been very widely used with over 1.7 million prescriptions issued since their listing on the Pharmaceutical Benefits Scheme in August 2000. Most of this use appears to be in addition to prescribing of the older NSAIDs rather than as a replacement for them. The purpose of this study is to compare the safety of the new COX-2 inhibitors with that of the older NSAIDs. We are interested in how often they cause renal failure and heart failure. The investigators will use well-established research methods to estimate the risk of heart failure and kidney failure with these drugs in the Australian community. Data from the study will form the basis of clinical practice guidelines for the safe use of these drugs in Australia.Read moreRead less
Self-limiting Anti-inflammatory Actions Of Glucocorticoids In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$377,036.00
Summary
Asthma is a disease characterised by excessive narrowing of the airway tubes resulting in difficulty exhaling air from the lungs. Symptoms of asthma include coughing, wheezing, shortness of breath and difficulty in breathing. Asthma affects almost 1 in 5 Australians and is especially prevelant in children. One in every three Australians will suffer from symptoms of asthma at some time in their life and despite current therapy, asthma is responsible for the deaths of more than 700 Australians eve ....Asthma is a disease characterised by excessive narrowing of the airway tubes resulting in difficulty exhaling air from the lungs. Symptoms of asthma include coughing, wheezing, shortness of breath and difficulty in breathing. Asthma affects almost 1 in 5 Australians and is especially prevelant in children. One in every three Australians will suffer from symptoms of asthma at some time in their life and despite current therapy, asthma is responsible for the deaths of more than 700 Australians every year. Airway tubes of asthmatics have more and larger contractile muscle cells lining the tubes. This increase in muscle mass results from chemicals that are released from white blood cells that migrate into the airway tubes during and after asthma attacks. This thickening slows airflow through the airway tubes because the muscle mass bulges into the holes of the tubes and when the muscle shortens the total diameter of the tubes decrease. We have recently shown that steroids used by asthmatics to treat the white blood cell contribution to the disease can reduce the growth of airway muscle. However, when the muscle has been pretreated with factors that are present in the inflamed airway, the anti-growth effects of steroids are prevented. This effect of the steroids is due to reduced production of a substance called prostaglandin E2 which can also reduce the growth of muscle. Thus, whilst steroids may help in treating some of the symptoms of asthma, they may be suboptimal in the treatment of muscle thickening and other aspects of the disease which involve cell division and multiplication. Our specific question in the next phase of this research is whether steroid inhibition of the release of prostaglandins compromises the useful actions of steroids on the growth of the airway tubes. The findings of this proposed study will provide new information on the role of steroids in asthma and may lead to better therapeutic strategies for the treatment of severe asthma.Read moreRead less