Nitroso-redox Imbalance In Glucocorticoid-induced Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$341,210.00
Summary
High blood pressure (hypertension) affects 20-30 % of Australian adults and in about 90-95 % of these individuals the hypertension is considered essential (cause unknown). Globally, it is the number 1 risk factor for death, and number 3 for disability (World Health Report 2002). The major consequences of hypertension are heart attack and stroke. Glucocorticoid (adrenal steroid hormone) induced hypertension and consequent cardiovascular morbidity-mortality is an important clinical problem. Althou ....High blood pressure (hypertension) affects 20-30 % of Australian adults and in about 90-95 % of these individuals the hypertension is considered essential (cause unknown). Globally, it is the number 1 risk factor for death, and number 3 for disability (World Health Report 2002). The major consequences of hypertension are heart attack and stroke. Glucocorticoid (adrenal steroid hormone) induced hypertension and consequent cardiovascular morbidity-mortality is an important clinical problem. Although naturally occurring glucocorticoid (GC) hypertension (Cushing's syndrome) is relatively rare, synthetic GC are widely used in clinical practice (in numerous inflammatory and autoimmune diseases and transplantation) and produce substantial cardiovascular morbidity and mortality. Further, abnormal GC breakdown (metabolism) and sensitivity to GC have been reported in around a third of essential hypertensive patients. We therefore need to understand how GC raise blood pressure and whether we can prevent and-or reverse these blood pressure raising effects. In the proposed studies, we will explore the role of relative deficiency of blood vessel dilating nitric oxide and nitric oxide inhibition by excess superoxide (nitroso-redox imbalance) in the genesis of GC hypertension. Further, we will identify agents known to be suitable for clinical use which are effective in preventing-reversing GC hypertension in the rat and are thus appropriate for clinical trials to prevent-reverse GC hypertension in humans. These studies will help answer the question of how GC raises blood pressure so that safer steroids can be designed, as well as identify agents that can potentially prevent or treat GC hypertension in humans.Read moreRead less
Age-Related Changes In Body Composition And Fuel Metabolism: The Role Of Glucocorticoid Signalling In Osteoblasts
Funder
National Health and Medical Research Council
Funding Amount
$820,528.00
Summary
Our previous studies suggest that age related changes in fat tissue could be due to an increased level of glucocorticoids within bone forming cells (osteoblasts). Mice in which the level of glucocorticoids in osteoblasts is selectively decreased were no different from normal mice at a young age but with ageing were protected against development of obesity and diabetes. This project will examine how bone influences age related changes in fat mass and examine ways in which this might be prevented.
Defining The Role Of GILZ In Inflammatory Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$675,030.00
Summary
Corticosteroids are commonly used to treat inflammatory diseases such as arthritis. Their action is based on effects on natural inflammation control pathways. One such pathway is that mediated by the protein known as GILZ (glucocorticoid induced leucine zipper). The function of this protein in disease is not well understood, and the research proposed here will increase understanding of its role. This knowledge could yield new treatments for arthritis and other inflammatory diseases.
Are Chondrocytes The Target Cells Of Glucocorticoid Therapy In Autoimmune Arthritis?
Funder
National Health and Medical Research Council
Funding Amount
$544,619.00
Summary
Glucocorticoids (GCs) are widely used for their potent anti-inflammatory and immunomodulatory effects due to the effects GCs on immune cells or synovial fibroblasts. Recently, we have made the exciting discovery that arthritis mice with glucocorticoid receptor knock-out in chondrocyte are completely resistant to glucocorticoid treatment. This study will identify the mechanisms underlying these hormonal effects with the aim to find new targets for efficient treatments for arthritis.
The Influence Of Glucocorticoid Hormones In T Cell Development And Function
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
The defence of the body to disease is a very complex process involving multiple interactions between subsets of white cells, in particular lymphocytes. This immune system, however, does not act in isolation but is subject to constant regulation by a variety of other cells and soluble factors. Particularly important in this regard is the impact of glucocorticoids which are normally associated with stress conditions. These steroids have been proposed to act at several levels in the immune system, ....The defence of the body to disease is a very complex process involving multiple interactions between subsets of white cells, in particular lymphocytes. This immune system, however, does not act in isolation but is subject to constant regulation by a variety of other cells and soluble factors. Particularly important in this regard is the impact of glucocorticoids which are normally associated with stress conditions. These steroids have been proposed to act at several levels in the immune system, usually causing suppression but they can also modify in a positive sense. Defining the targets of glucocorticoids and their precise functional impact will thus have very important implications for not only understanding the regulation of the immune response but also in the clinic. This project will make use of mice which have had the receptor for glucocorticoids genetically deleted. Focussing on T cells (the most important cells of the immune system) these mice will be examined in detail for alterations in the development of T lymphocytes and their function in defending the body against virus and tumours and their involvement in self destruction (autoimmune) diseases including multiple sclerosis.Read moreRead less