Molecular Characterisation Of Adiponectin Receptors: Implications For Adiponectin Action And Resistance
Funder
National Health and Medical Research Council
Funding Amount
$95,137.00
Summary
Adiponectin is a hormone secreted by fat cells with anti-inflammatory, anti-atherogenic and insulin sensitising properties. Adiponectin levels and actions are compromised in obesity and type 2 diabetes. Adponectin mediates its effects via two receptors but the mechanisms are poorly understood. This proposal aims to define the underlying mechanisms with the ultimate goal of identifying novel therapeutic strategies to improve adiponectin's actions.
Mineralocorticoid Receptors - Mechanisms Of Ligand- And Tissue- Specific Activation
Funder
National Health and Medical Research Council
Funding Amount
$126,848.00
Summary
Heart disease is a major cause of death and economic burden in Australia and throughout the world. The steroid hormone aldosterone controls salt and water balance, blood pressure and has a significant role in heart failure. Although drugs that block the aldosterone receptor significantly help patients with heart failure, their use is limited by side effects. This work will identify the profile of proteins that promote aldosterone effects and enable the development of heart-specific blockers.
Genetic Programs Regulated By The Nuclear Hormone Receptor, LXR, In Muscle: Control Of Cholesterol And Lipid Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholester ....The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholesterol levels are characteristic of lipotoxic diseases. HDLs have a defensive role in the prevention of atherogenic dyslipidemia by mediating cholesterol efflux from peripheral tissues through the hormone -dependent ATP-binding cassette (ABC) transporters back to the liver for excretion and elimination. Agents that raise the levels of high density lipoprotein cholesterol (HDLc) through cholesterol efflux provide a pharmaceutical solution for the prevention of hypercholesterolemia, atherogenic and cardiovascular disease. These hormone dependent cholesterol and lipid effluxing proteins are regulated by a protein named LXR. Understanding the functional role of LXR in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body cholesterol homeostasis and lipid metabolism. Furthermore, LXR and LXR target genes that facilitate cholesterol efflux and consequently raise HDLc levels are important pharmaceutical targets. Identification of novel LXR targets in skeletal muscle, which has a significant role in insulin sensitivity and the blood lipid profile provides an additional platform for therapeutic intervention.Read moreRead less
Modulation Of Cytoskeletal Structure By Progesterone Receptor Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$337,650.00
Summary
Ovarian hormones are fundamental regulators of normal cell growth and differentiation, and crucial to the development and progression of breast cancer. We have recently shown that the ovarian hormone progesterone can influence the expression of proteins in the cell scaffolding, known as the cytoskeleton. The cytoskeleton is responsible for maintaining cell shape, and there is growing evidence that alterations in the cytoskeleton can actually cause normal cells to become cancerous. We have shown ....Ovarian hormones are fundamental regulators of normal cell growth and differentiation, and crucial to the development and progression of breast cancer. We have recently shown that the ovarian hormone progesterone can influence the expression of proteins in the cell scaffolding, known as the cytoskeleton. The cytoskeleton is responsible for maintaining cell shape, and there is growing evidence that alterations in the cytoskeleton can actually cause normal cells to become cancerous. We have shown that progesterone affects the levels of a cytoskeletal protein called tropomyosin, which plays a pivotal role in cell shape maintenance. We have hypothesised that this effect may be important in the cell shape changes in breast cancer that lead to metastasis. In this grant, we will investigate the role of the progesterone receptor in controlling the expression of the cytokeleton; we will investigate whether cell shape changes caused by progesterone cause more aggressive behaviour in breast cancer cells and we will determine whether there are changes in cytokeletal proteins in breast tumours. This will provide a rational basis for further studies aimed at delineating the significance of hormonal regulation of cell architecture.Read moreRead less
Progesterone Signalling In Normal And Malignant Breast Relies On Chromosomal Positioning Of Progesterone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$569,346.00
Summary
The cell nucleus carries genetic information that directs cell function. The nucleus is organised into compartments, which are altered in breast cancer, leading to altered function. The ovarian hormone progesterone acts via a receptor, which clumps into foci in the nucleus when active. In cancers, this clumping is disrupted. In this project we will work out how these foci control cell function, and how this leads to the specific functions of progesterone in normal breast and breast cancers.
NR1F (ROR) Nuclear Hormone Receptors And Metabolism: Insights Into The Control Of Lipid Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
ROR is a member of a gene family, that regulates reproduction, endocrine physiology, and metabolism, and are important in human health. ROR function remains illusive. However, it is expressed in liver, fat and muscle, tissues that (i) modulate blood lipids, insulin sensitivity and energy balance, and (ii) have an important role in diabetes and obesity. Understanding ROR function in metabolism provides the opportunity for the discovery of new pathways that ameliorate metabolic disease.
Molecular Regulation Of Metabolism And Body Composition By Ski Via Crosstalk With Nuclear Hormone Receptor Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Obesity is a common and burdensome health problem in the community which leads to diabetes and heart disease. A number of factors, including hormones play important roles in determing risk of obesity. This study proposes to investigate whether the Ski gene which is a regulatory factor for many hormones affects metabolism in transgenic mouse models of altered Ski function. The proposed studies may identify Ski as a target for therapy for obesity and improvement in sketal muscle metabolism.
The Physiological Relevance Of Calcitonin In Osteoclast Function
Funder
National Health and Medical Research Council
Funding Amount
$437,640.00
Summary
Throughout adult life, bone tissue is continuously remodelled. The two main processes involved in bone remodelling, are bone formation and bone breakdown. Bone formation is controlled by cells known as osteoblasts and bone breakdown is controlled by cells known as osteoclasts. Under normal circumstances these two processes are tightly coupled. Excessive breakdown of bone, causes these two processes to become unbalanced and results in bone loss. This is the basis of many bone diseases such as ost ....Throughout adult life, bone tissue is continuously remodelled. The two main processes involved in bone remodelling, are bone formation and bone breakdown. Bone formation is controlled by cells known as osteoblasts and bone breakdown is controlled by cells known as osteoclasts. Under normal circumstances these two processes are tightly coupled. Excessive breakdown of bone, causes these two processes to become unbalanced and results in bone loss. This is the basis of many bone diseases such as osteoporosis, a condition in which the bones become fragile and therefore more susceptible to fracture. 1 in 2 women and 1 in 5 men aged 70 years and older suffer from osteoporosis in Australia. Despite this, the mechanisms which control osteoclast breakdown of bone are not well understood. Our laboratory is interested in how hormones affect osteoclast action. We plan to examine the role of the hormone calcitonin, thought to be important inhibitor of osteoclastic bone breakdown. This will be achieved by studying transgenic mice in which the receptor for calcitonin is specifically removed from osteoclasts. This will allow us to precisely determine the role of calcitonin in osteoclast function. Current treatment for osteoporosis involves the administration of drugs which inhibit bone breakdown. This project will increase our understanding of how calcitonin acts to regulate the function of osteoclasts. We believe that this research is of great importance as osteoporosis is becoming more prevalent as the population ages.Read moreRead less
The Role Of The Endothelium In Insulin's In Vivo Action Upon Skeletal Muscle Metabolism.
Funder
National Health and Medical Research Council
Funding Amount
$451,500.00
Summary
A number of studies using novel techniques developed in association with our USA collaborators, indicate that insulin has a major stimulatory effect on blood flow within muscle in both animals and humans to improve access for itself as well as nutrients such as glucose. As much as 50% of the glucose taken up by muscle in vivo during continual exposure to insulin may be attributed to this effect. Moreover, this haemodynamic effect of insulin in muscle is impaired in a number of animal models and ....A number of studies using novel techniques developed in association with our USA collaborators, indicate that insulin has a major stimulatory effect on blood flow within muscle in both animals and humans to improve access for itself as well as nutrients such as glucose. As much as 50% of the glucose taken up by muscle in vivo during continual exposure to insulin may be attributed to this effect. Moreover, this haemodynamic effect of insulin in muscle is impaired in a number of animal models and in obese humans when insulin mediated muscle glucose uptake is also impaired. What is not known is how insulin mediates this haemodynamic effect of recruiting capillary blood flow. Thus in the present study a number of aspects are to be explored, with particular focus on the cells that line the blood vessels and constitute the capillaries, the so called endothelium. First, we will explore the specific role of the endothelium in insulin's action by using the novel approach of attaching insulin to a large molecule that prevents it leaving the lumen of the blood vessel. This will mean that insulin will be confined to interacting only with insulin receptors on the muscle endothelium. Similarly, non activating anti insulin receptor antibody will be used in the presence of insulin to selectively prevent activation of the endothelial insulin receptors. In addition, we will investigate whether homocysteine, an amino acid found to impair endothelial dependent vasodilatation, impairs the haemodynamic effects of insulin. The impact that normal insulin release after a meal has upon the haemodynamic actions in muscle and the role this has in muscle glucose uptake will also be investigated by using the techniques developed in the first part of the project. Our over riding hypothesis is that the endothelium plays a key role in controlling insulin and possibly glucose access to muscle cells and thus a significant proportion of insulin mediated metabolic events in muscle.Read moreRead less
Steroid hormones, such as oestrogen and cortisol, act in the body by binding a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified termed SRA, which remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins t ....Steroid hormones, such as oestrogen and cortisol, act in the body by binding a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified termed SRA, which remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins that bind to SRA in cancer cells, and may well play a critical role in regulating how SRA modulates genes. This project seeks to understand how this family interacts with SRA, the functional effects on breast cancer cells, and the detailed 3-dimensional structure of the family members coupled with SRA. This work will provide novel insight into how SRA regulates steroid hormone action, and may create new potential avenues for developing therapeutics in breast cancer.Read moreRead less