Post Transcriptional Regulation Of The Plasminogen Activator Inhibitor Type 2 Gene
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins, mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the most important enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its activ ....The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins, mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the most important enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA). Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that inhibits u-PA activity. The degree of u-PA activity therefore depends on the relative levels of u-PA and PAI-2. In addition to controlling u-PA activity, PAI-2 also influences intracellular events including cell proliferation, differentiation and apoptosis. PAI-2 protein and mRNA levels are substantially modulated by many cytokines and growth factors. This project addresses the molecular mechanisms underlying the regulation of PAI-2 gene expression. We have recently shown that a significant degree of PAI-2 regulation occurs at the level of PAI-2 mRNA stability, and we have identified two regions within the PAI-2 mRNA that play a role in this process. Both regions provide binding sites for cellular proteins. We have identified one of these binding proteins to be HuR, a protein that has recently been shown to control the stability of other mRNAs. The specific aims of this project are firstly, to determine the role of HuR in the control of PAI-2 mRNA stability, and secondly, to clone a characterise the other PAI-2 mRNA binding proteins we have identifed. An understanding of how cells modulate levels of PAI-2 mRNA will significantly add to the broader field of gene regulation and may also provide new clues to influence PAI-2 levels in the body.Read moreRead less
Short-term Effects Of Overfeeding On Metabolic Risk In Humans
Funder
National Health and Medical Research Council
Funding Amount
$417,196.00
Summary
The prevalence of obesity is rapidly increasing in Australia and other parts of the world. Obesity is closely associated with insulin resistance and plays a role in the development of type 2 diabetes. However, the effects of short-term periods of over nutrition in humans remain unclear. In the proposed study, we will investigate the effects of short-term weight gain by high fat feeding in lean subjects, in subjects who are overweight and in subjects who are genetically more likely to develop dia ....The prevalence of obesity is rapidly increasing in Australia and other parts of the world. Obesity is closely associated with insulin resistance and plays a role in the development of type 2 diabetes. However, the effects of short-term periods of over nutrition in humans remain unclear. In the proposed study, we will investigate the effects of short-term weight gain by high fat feeding in lean subjects, in subjects who are overweight and in subjects who are genetically more likely to develop diabetes (due to strong family history). The aims are to distinguish physiological and endocrine characteristics of individuals who store more fat in response to overfeeding. We will identify differences between these individuals and whether they have defects in upregulating machinery involved in fat oxidation and energy production in skeletal muscle that may help them adapt during to energy excess. We will look for changes in type 2 diabetes risk and we will have the potential to identify defects in factors that are involved in this response. We will also re-examine indivudals again after calorie restriction and weight loss. We also plan to confirm the role of the candidate genes involved in fat oxidation that have been identifieid in human studies by in vivo gene transfer technology in rodents. This study will determine whether overweight and lean subjects behave similarly when faced with an overfeeding challenge. We expect that individuals with a genetic predisposition for T2DM will become more IR, due to metabolic inflexibility and a decreased ability to upregulate machinery involved in fatty acid oxidation and mitochondrial function. By characterising the physiological and endocrine responses to overfeeding, we will establish quantifiable markers allowing us to distinguish those at risk and identify new targets for pharmacological or lifestyle intervention.Read moreRead less
Mechanisms Of Repair And Adaptation In The Gastric Mucosa: Roles Of COX-2 And Growth Factors
Funder
National Health and Medical Research Council
Funding Amount
$391,650.00
Summary
The stomach lining is continually threatened by its own acid and by hazards such as bacteria and ingested drugs. The drugs called COX inhibitors, which include aspirin, are widely used for treating arthritis and other inflammatory diseases and for preventing heart attacks and strokes. Despite their value in these conditions, COX inhibitors are responsible for about 5-10,000 hospital admissions annually in Australia due to complications from the side effect of stomach ulcers. A recent advance has ....The stomach lining is continually threatened by its own acid and by hazards such as bacteria and ingested drugs. The drugs called COX inhibitors, which include aspirin, are widely used for treating arthritis and other inflammatory diseases and for preventing heart attacks and strokes. Despite their value in these conditions, COX inhibitors are responsible for about 5-10,000 hospital admissions annually in Australia due to complications from the side effect of stomach ulcers. A recent advance has been the development of a sub-class called COX-2 inhibitors. In a very short time, one of these has become among the most prescribed drugs in Australia. The advantage of the COX-2 inhibitors is that they produce many less stomach ulcers. However, they have only been tested in patients who have not had a recent history of ulcer. Our preliminary experiments, together with some related information from two overseas groups, suggests that COX-2 is useful in the stomach, and is markedly increased around a healing ulcer. Our data suggest that blocking it delays the healing of experimental ulcers. This project aims to understand the roles of COX-2 in the stomach, and to clarify the effects of inhibiting it when the stomach is damaged or threatened. The project will also look for links between COX-2's functions and another protective process we have discovered called 'adaptation'. When anti-inflammatory drugs are given regularly to rats or humans under certain conditions, the stomach develops resistance after a few days so that the damage caused by each subsequent dose is markedly reduced. We have uncovered a number of mechanisms responsible for this during a current NH and MRC grant, and plan to explore some of the leads this work has given. The SIGNIFICANCE of the project is its potential to lead to safer use of anti-inflammatory drugs or eventually to new agents, and its potential to give new knowledge about how the lining of organs such as the stomach protects itself.Read moreRead less
Does Loss Of Melanocortin Glucose Sensing Contribute To Obesity Induced Diabetes?
Funder
National Health and Medical Research Council
Funding Amount
$617,531.00
Summary
Diabetes is a failure to properly regulate blood glucose levels. Escalating rates of diabetes are a major health problem. Melanocortin neurons in the brain detect blood sugar levels and usually regulate glucose production and utilization, but in obese animals they do not. We have developed a possible therapeutic, which appears to reverse the glucose insensitivity, and rapidly reduces blood glucose in diabetic mice. This project will determine how melanocortins act to regulate glucose levels
Gene Variants In Adiponectin And Its Receptors As Risk Factors For Metabolic And Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$534,107.00
Summary
Obesity has a major impact on the development of metabolic syndrome (MetS), type 2 diabetes (T2D), and cardiovascular disease (CVD). It is important to identify the molecular links between obesity and these conditions. Adiponectin, an adipocyte-specific hormone, is a likely molecular candidate because of its pleiotropic metabolic actions. We will investigate the role of adiponectin, the variants within its gene ADIPOQ, and that of its two receptors, in the development of MetS, T2D, and CVD.