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
I am a biochemist - cell biologist investigating the molecular coordination of cellular processes that regulate metabolism. My research aim is to identify and validate novel therapeutic targets - strategies that will ameliorate the metabolic complications
The Mechanism Of Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$679,500.00
Summary
Growth hormone GH excess or deficit results in considerably shortened lifespan. While cardiovascular disease is a major element in this mortality, GH status has also been linked to kidney disease and diabetic retinopathy. Importantly, GH produced locally in breast cells and prostate cells transform s these cells, creating cancers. We aim to define how GH activates its receptor, to facilitate a GH antagonist which results from understanding how GH activates its cell surface receptor.
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
Genetic Programs Induced By The Nuclear Hormone Receptor PPARdelta In Muscle: Control Of Lipid And Energy Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of d ....Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of dyslipidemia by mediating cholesterol efflux from tissues. In contrast, the LDLs accumulate in the arterial wall leading to atherosclerosis. Physiological maintenance of lipid homeostasis requires a dynamic balance between metabolic signalling cascades, diet, lifestyle etc. PPPARs are nuclear hormone receptors that function as fatty acid activated transcription factors that regulate lipid and cholesterol homeostasis. PPARs are bona fide targets for the development of therapeutic compounds useful in the treatment of lipid disorders. PPAR delta is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight. Muscle is a major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeostasis and HDL levels. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile and lipid metabolism. Understanding the functional role of PPAR delta in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body lipid homeostasis. Understsanding these receptors may provide a pharmaceutical solution for the prevention of hyper-lipidemia--cholesterolemia, and atherogenic disease. Moreover, it may lead to the identification of agents that influence a major mass tissue in terms of lipid absorption, and increased fatty acid oxidation, and consequently normalize the blood lipid profile.Read moreRead less
Regulation And Functional Roles Of ADAM 10 Protease In Prostate Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cel ....Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cells to break free from their original tissue positions, walk through surrounding tissue and deposit themselves at distant sites to form a secondary tumour. In this research we are looking at a protein, called ADAM-10, which belongs to a family of proteases, the ADAMs, which contain both A Disintegrin And Metalloprotease activity, hence their name. Our data suggest ADAM-10 is produced in large quantities by prostate cancer cells but can be differently located within these cells it sits on the outer membrane of normal or benign prostate glands but re-locates to the cell nucleus in high grade prostate cancer cells. We have also identified ADAM-10 protein in small membrane fragments that are commonly shed from prostate cancer cells. Preliminary evidence suggests that levels of ADAM-10 in each of these locations is regulated by growth factors and-or the male sex hormone, androgen, key hormones involved in prostate cancer growth and progression. We do not yet know what actions ADAM-10 has when it occurs in these different locations but believe the membrane form will be involved in metastasis, with the nuclear form being involved in regulating events within the nucleus, the control centre for the cell. This grant application aims to build on our novel observations and investigate the underlying mechanisms of ADAM-10 hormonal regulation and function. If proven, these issues may be important for the development, progression and future treatment of prostate cancer.Read moreRead less
Genetic And Metabolic Determinants Of Spontaneous Physical Activity
Funder
National Health and Medical Research Council
Funding Amount
$67,828.00
Summary
It could be argued that obesity is the most significant public health problem facing Australians today. Almost one in five adult Australians are obese, making them highly susceptible to diabetes, coronary heart disease, high blood pressure, high blood lipid levels, and some cancers, as well as reduced psychosocial health. There is therefore an urgent need to reduce the prevalence of obesity in our society. Unfortunately, attempts to sustain significant weight loss by dieting and exercise are nea ....It could be argued that obesity is the most significant public health problem facing Australians today. Almost one in five adult Australians are obese, making them highly susceptible to diabetes, coronary heart disease, high blood pressure, high blood lipid levels, and some cancers, as well as reduced psychosocial health. There is therefore an urgent need to reduce the prevalence of obesity in our society. Unfortunately, attempts to sustain significant weight loss by dieting and exercise are nearly always unsuccessful and none of the anti-obesity drugs currently on the market are safe to use long-term. Effective treatments for obesity are only likely to be developed once we understand more about what controls body weight regulation. An inactive lifestyle is clearly a risk factor for obesity. Spontaneous physical activity (or activity associated with daily life, as opposed to formal exercise) can play a major role in determining body weight. Recent work suggests that spontaneous physical activity is influenced not only by our environment but by our biological makeup as well (i.e. genetic and metabolic factors). The aim of this study is to investigate what some of these factors are, and whether they are responsible for altering body weight regulation in animal models of obesity. Specifically we will be looking at whether spontaneous physical activity is influenced by circulating hormones (such as leptin, oestrogen, and pancreatic polypeptide) and a messenger molecule (nitric oxide), and we will also identify genes which influence physical activity in a mouse model of obesity. By examining the genetic and metabolic basis of inactivity in obese rodent models, this project will further our understanding of how energy balance is disturbed in obesity in the hope of developing better therapies to treat obesity in the future.Read moreRead less