Regulation of large artery stiffness by endothelium-derived mediators and effects on the arterial pressure waveform. Stiffening of arteries is an important cardiovascular risk factor and increases with age, high blood pressure, high cholesterol and diabetes. Cells that line the blood vessels (endothelial cells), become damaged and this reduces the available amount of a dilator substance, nitric oxide, and increases the activity of a constrictor substance, endothelin-1. We have shown that nitric ....Regulation of large artery stiffness by endothelium-derived mediators and effects on the arterial pressure waveform. Stiffening of arteries is an important cardiovascular risk factor and increases with age, high blood pressure, high cholesterol and diabetes. Cells that line the blood vessels (endothelial cells), become damaged and this reduces the available amount of a dilator substance, nitric oxide, and increases the activity of a constrictor substance, endothelin-1. We have shown that nitric oxide regulates large artery stiffness and we believe that other endothelial mediators are also important regulators. Therefore, we aim to explore this in a series of studies. Regulation of stiffness of large arteries will improve treatment of age-related cardiovascular disease (eg isolated systolic hypertension)Read moreRead less
Bias and allostery at the calcium sensing receptor. This project aims to provide a mechanistic and dynamic picture of the structure, function and physiology of the human calcium sensing receptor (CaSR), which is critical for vertebrate life. By responding to chemicals in the body, it acts as a universal nutrient sensor to maintain extracellular calcium homeostasis and mediate biological functions, including neurotransmission, inflammation, digestion, blood pressure and development. However, it i ....Bias and allostery at the calcium sensing receptor. This project aims to provide a mechanistic and dynamic picture of the structure, function and physiology of the human calcium sensing receptor (CaSR), which is critical for vertebrate life. By responding to chemicals in the body, it acts as a universal nutrient sensor to maintain extracellular calcium homeostasis and mediate biological functions, including neurotransmission, inflammation, digestion, blood pressure and development. However, it is not known how this single receptor controls the actions of multiple ligands to mediate numerous functions. By elucidating the roles of the CaSR and its ligands, this project aims to better understand fundamental physiological processes.Read moreRead less
Oxytocin receptor PET ligands: imaging the love receptor’s engagement. This project aims to develop a positron emission tomography (PET) ligand for the oxytocin receptor. This novel platform is significant as it will allow the scientific community to answer questions about the role of the oxytocin receptor in the important process of social behaviour which underlies quality of life. This knowledge gap has remained unanswered for decades due to the lack of specific techniques to measure oxytocin ....Oxytocin receptor PET ligands: imaging the love receptor’s engagement. This project aims to develop a positron emission tomography (PET) ligand for the oxytocin receptor. This novel platform is significant as it will allow the scientific community to answer questions about the role of the oxytocin receptor in the important process of social behaviour which underlies quality of life. This knowledge gap has remained unanswered for decades due to the lack of specific techniques to measure oxytocin receptor engagement. It is also significant as it will equip Australian startup Kinoxis Therapeutics to progress their molecules to market, a process enabled by measuring oxytocin receptor engagement. Our dual expertise on the oxytocin receptor and PET ligand development uniquely situate us to generate this technology.Read moreRead less
The combined use of proteomics and small molecules for target identification and pathway analysis. This project intends to investigate how a series of new small molecules identified from our research to improve the metabolic effects of insulin. This project will integrate medicinal chemistry with proteomics and metabolic biology to identify the cellular targets and their mechanism of action.
Improving diagnostic accuracy and treatment options for equine PPID. Equine Pituitary Pars Intermedia Dysfunction (PPID) is a common, chronic and potentially life-threatening disease of older horses and ponies. Although a treatment is available, the disease is poorly understood and there are some concerns that the current diagnostic technology is not delivering accurate results. Thus, this project aims to develop a more accurate diagnostic test for PPID, while exploring the relationship between ....Improving diagnostic accuracy and treatment options for equine PPID. Equine Pituitary Pars Intermedia Dysfunction (PPID) is a common, chronic and potentially life-threatening disease of older horses and ponies. Although a treatment is available, the disease is poorly understood and there are some concerns that the current diagnostic technology is not delivering accurate results. Thus, this project aims to develop a more accurate diagnostic test for PPID, while exploring the relationship between PPID and metabolic syndrome, to generate new insights into the cause and consequences of both diseases. As an added benefit, the project will assist horseracing laboratories to improve their detection methods for peptide doping in younger competition horses.
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Does Early Overnutrition Differentially Alter Hypothalamic Neuropeptides That Regulate Food Intake In The Rat
Funder
National Health and Medical Research Council
Funding Amount
$346,250.00
Summary
In Australia the incidence of obesity, in particular childhood obesity, is increasing dramatically, and the possible long term consequences of this are of great concern. The brain regulates appetite through a number of chemical transmitters such as neuropeptide Y (NPY) which is present in the brains of mammals and causes increased food intake. The effects of overeating from a young age on these brain transmitters has been largely ignored although this may impact on subsequent eating behaviour. I ....In Australia the incidence of obesity, in particular childhood obesity, is increasing dramatically, and the possible long term consequences of this are of great concern. The brain regulates appetite through a number of chemical transmitters such as neuropeptide Y (NPY) which is present in the brains of mammals and causes increased food intake. The effects of overeating from a young age on these brain transmitters has been largely ignored although this may impact on subsequent eating behaviour. In addition to NPY we will study other transmitters in the brain that have profound effects on appetite, some increasing, and others decreasing, food intake. These may form useful therapeutic targets for new drugs for obesity. Key targets we will study include melanocortins, glucagon-like peptide 1, urocortin, melanin concentrating hormone, agouti related peptide, and NPY. We will determine whether overnutrition from birth to weaning leads to changes in these appetite regulating neurotransmitters in the brain, and monitor the hormonal signals that impact on their activity. We will also determine whether early overnutrition exacerbates the subsequent responses to a high fat diet by comparison with rats made obese as adults. We will measure brain concentrations of the neurotransmitters, the amount released from the brain, and determine whether the feeding responses to injections of these agents is altered in obese animals. We have evidence that these transmitters interact in a co-ordinated fashion to affect feeding; this project will examine whether these interactions are maintained in the various types of obesity. Rats are commonly used for this type of study as the processes regulating feeding are very similar to those in humans and these agents cause similar effects in rats and humans. It is hoped that this information will provide new insight into the way brain adapts to overnutrition, and provide potential treatments for obesity and other feeding disorders.Read moreRead less
NPY Suppresses Seizures And Modulates Thalamocortical Activity In Animal Models Of Generalized Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$386,020.00
Summary
Epilepsy is the most common serious chronic neurological disease in the community, affecting up to 3% of the population in a lifetime and 0.5-1% at any one time. Absence epilepsy is one of the most common types of epilepsy, most frequently seen in childhood and teenage years that may persist into adulthood. Anti-epileptic drugs are effective in controlling absence seizures in most patients, however there is an important group (20-40%) of patients in whom the absence seizures remain uncontrolled ....Epilepsy is the most common serious chronic neurological disease in the community, affecting up to 3% of the population in a lifetime and 0.5-1% at any one time. Absence epilepsy is one of the most common types of epilepsy, most frequently seen in childhood and teenage years that may persist into adulthood. Anti-epileptic drugs are effective in controlling absence seizures in most patients, however there is an important group (20-40%) of patients in whom the absence seizures remain uncontrolled with current medications. Recently there has been considerable interest in the role that chemical in the brain, such as neuropeptide Y (NPY), may play in epilepsy. The research proposed will examine the role of NPY in several animal models of absence epilepsy. We have recently shown that NPY suppresses absence seizures in a rat genetic model of generalised epilepsy, and that this appears to be mediated by Y2 receptors. This work will build on these novel findings, and determine the localisation of the effect within the brain, and the underlying mechanism. We will check NPY effects across several models in different species, a genetic rat model with spontaneous seizures, and in mice treated with a chemical to induce seizures. This will determine its broad applicability. We will also determine the effects of removal of NPY or NPY receptors on the effects of NPY on seizure expression. Finally, brain recording techniques will be applied to determine the mechanism and site within the brain underlying the protective actions of NPY. The project has the potential to provide novel insights into the role of NPY in the expression and modulation of absence seizures. NPY related mechanisms might represent targets for the development of a new class of therapeutic agents for the treatment of absence epilepsy. Targets that are identified as being important in the expression of absence seizures may also prove to be relevant in other types of generalised epilepsy syndromes.Read moreRead less
Discovery And Development Of Better Pain Treatments
Funder
National Health and Medical Research Council
Funding Amount
$9,613,850.00
Summary
Many forms of pain remain poorly treated, leading to significant quality of life and economic losses. This Program grant will discover and characterise new peptides from cone snails and spiders that modulate specific channels in nerves that are critical to the transmission of pain signals to the brain. Using advanced chemical and structural approaches, promising leads will be optimised for potency and stability and evaluated in disease and pathway-specific models of pain to establish their clini ....Many forms of pain remain poorly treated, leading to significant quality of life and economic losses. This Program grant will discover and characterise new peptides from cone snails and spiders that modulate specific channels in nerves that are critical to the transmission of pain signals to the brain. Using advanced chemical and structural approaches, promising leads will be optimised for potency and stability and evaluated in disease and pathway-specific models of pain to establish their clinical potential.Read moreRead less
Sex Hormones And Heart Disease In Older Women Study (The SHOW Study)
Funder
National Health and Medical Research Council
Funding Amount
$594,672.00
Summary
Cardiovascular disease (CVD, heart disease and stroke) is the leading cause of death in women aged 65 and over. Counter-intuitively, androgens may be as, or even more important, than estrogens in determining CVD risk and all-cause mortality in women, but this is yet to be verified. We will document blood levels of androgens in women aged 70+ and determine whether androgens are associated with CVD and death in this large cohort of elderly well women.
I am an academic endocrinologist and clinician. I lead a large research program that investigates the links between hormones and diseases of ageing in women. Thus my research program addresses the contribution of changes in adrenal and ovarian steroids in