Allosteric Regulation Of G Protein-coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$509,017.00
Summary
The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of these stimuli acting on cells do so not by directly entering the cells, but rather by acting on specific types of receiver proteins on the cell's surface that are called receptors. The most important family of cell-surface receptors transmit their message to the inside of the cell by coupling to yet another type of protein kno ....The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of these stimuli acting on cells do so not by directly entering the cells, but rather by acting on specific types of receiver proteins on the cell's surface that are called receptors. The most important family of cell-surface receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as a G protein, and are therefore commonly referred to as G protein-coupled receptors (or GPCRs). Aberrations in the normal function of these GPCRs have been implicated in a wide variety of disorders, including neuropsychiatric conditions, endocrine disorders, cardiovascular disease and many cancers. To date, the majority of drugs acting at GPCRs do so by binding to specific regions on these receptors. Although many breakthroughs in disease treatment have been achieved using this approach, there remain a number of acknowledged limitations, including lack of drug selectivity, toxicity and reduced responsiveness with prolonged therapy. Our current proposal focuses on targeting drugs to alternative regions of GPCRs that may overcome many of the limitations associated with current drug therapies. An understanding of the properties of these alternative drug binding sites, which will be investigated in our current grant, can lead to more effective treatments for a variety of diseases.Read moreRead less
Understanding Cell Signalling Mechanisms Activated By Relaxin Family Peptides: Targets With Therapeutic Potential
Funder
National Health and Medical Research Council
Funding Amount
$306,842.00
Summary
One of the most powerful ways that the activity of the cells that make up the tissues and organs of the body can be changed is by the interaction of chemicals with proteins called receptors located at the cell surface. The commonest type of receptor is called a G-protein coupled receptor as it is linked to mechanisms inside the cell by the G-proteins. These receptors are the most commonly targeted by pharmaceutical companies that wish to alter the responses of cells for therapeutic purposes and ....One of the most powerful ways that the activity of the cells that make up the tissues and organs of the body can be changed is by the interaction of chemicals with proteins called receptors located at the cell surface. The commonest type of receptor is called a G-protein coupled receptor as it is linked to mechanisms inside the cell by the G-proteins. These receptors are the most commonly targeted by pharmaceutical companies that wish to alter the responses of cells for therapeutic purposes and almost 2-3 of all drugs currently marketed work through these proteins. This project will examine the mechanisms whereby certain types of G-protein coupled receptor produce signals in cells and determine what are the critical areas of the receptor for these interactions. The receptors involved have been discovered only in the last 4 years and little is known of the ways these change the activity of cells. The substances acting on these receptors have potential for development as targets for drugs that have the potential to treat fibrosis which is a feature of many diseases including cardiac failure, kidney failure and lung disease.Read moreRead less
Determinants Of Binding And Activity Of G-protein Coupled Receptors RXFP1 And RXFP2; The Receptors For Relaxin And INSL3
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
Relaxin is a hormone which has long been known to have essential roles in pregnancy and birth. However it has also been demonstrated to have far broader involvement in the functioning of the kidney, heart and central nervous system. It is currently in clinical trials with our commercial partner BAS Medical for the treatment of congestive heart failure, cervical ripening and preeclampsia. Furthermore, relaxin shows enormous promise as an antifibrotic agent which has far-reaching therapeutic conse ....Relaxin is a hormone which has long been known to have essential roles in pregnancy and birth. However it has also been demonstrated to have far broader involvement in the functioning of the kidney, heart and central nervous system. It is currently in clinical trials with our commercial partner BAS Medical for the treatment of congestive heart failure, cervical ripening and preeclampsia. Furthermore, relaxin shows enormous promise as an antifibrotic agent which has far-reaching therapeutic consequences since fibrosis is a hallmark of all forms of progressive cardiovascular and renal disease and obstructive airway disease (asthma), which collectively contribute to 40-50% of deaths in developed countries. Research into the mechanisms whereby relaxin exerts its cellular effects has been limited by the inability of researchers to identify its receptor. We now know that relaxin acts through a novel G-protein coupled receptor (GPCR) Relaxin Family Peptide Receptor (RXFP) RXFP1 and will also acts on a related receptor RXFP2. The RXFP2 receptor is actually the receptor for a hormone with similarities to relaxin, INSL3. It is essential that an appreciation of RXFP receptor function is obtained not only for its important actions in pregnancy, but also for its clinical applications. In this regard, improved understanding of how relaxin and INSL3 interact with their receptors and how these receptors function is essential. We will continue our previously successful approaches to study the interaction of relaxin and INSL3 with these receptors and the mechanisms by which the receptors function. The knowledge gained will aid in the design of smaller, more potent and orally active forms of relaxin and INSL3 for future clinical applications. This multi-disciplinary approach will allow us to fully maximise the clinical potential of this enigmatic hormone.Read moreRead less
Novel Modes Of Regulating Serotonin 5HT2c Receptors.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of these stimuli acting on cells do so not by directly entering the cells, but rather by acting on specific types of receiver proteins on the cell's surface that are called receptors. The most important family of cell-surface receptors transmit their message to the inside of the cell by coupling to yet another type of protein kno ....The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of these stimuli acting on cells do so not by directly entering the cells, but rather by acting on specific types of receiver proteins on the cell's surface that are called receptors. The most important family of cell-surface receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as a G protein, and are therefore commonly referred to as G protein-coupled receptors (or GPCRs). The current proposal focuses on a special family of GPCRs that mediate the actions of the neurochemical, serotonin (or 5HT), in the human brain. These serotonin GPCRs are major targets for antidepressant and antipsychotic medications, and also play a role in anxiety, migraine and the control of appetite. Despite the important role of serotonin GPCRs in health and disease, the mechanism of action of many drugs acting on these receptors remain unknown. Our project will specifically investigate novel molecular mechanisms associated with serotonin GPCR activity that may prove vital in understanding mechanisms of psychiatric illnesses, and how many psychiatric medicines actually work.Read moreRead less
Therapeutic Relevance Of AT2 Receptors In Cardiovascular Disease And Aging
Funder
National Health and Medical Research Council
Funding Amount
$519,279.00
Summary
Pharmacological modulation of the renin angiotensin system is a cornerstone of evidence-based cardiovascular therapeutics. However, their molecular mechanisms are not entirely clear and some therapeutic options have not been utilized to their full potential. The hormone angiotensin II causes both excitatory and inhibitory cardiovascular effects via distinct binding sites. Of particular importance to contemporary society is the shift in the demographic to a more aged population. In Australia in 2 ....Pharmacological modulation of the renin angiotensin system is a cornerstone of evidence-based cardiovascular therapeutics. However, their molecular mechanisms are not entirely clear and some therapeutic options have not been utilized to their full potential. The hormone angiotensin II causes both excitatory and inhibitory cardiovascular effects via distinct binding sites. Of particular importance to contemporary society is the shift in the demographic to a more aged population. In Australia in 2002, 13% of the population (~2.5 million) were aged 65 years or over, and it has been estimated that this number will increase to 18% (~4 million) by the year 2021. While lipid status and smoking are well known risk factors for cardiovascular disease, advanced age by far confers the greatest risk for cardiovascular disease. In this context, we have found a greater role of the inhibitory angiotensin II binding site in aging that may result from breakdown products of angiotensin II having their own unique effects. This project will determine the relative role of various angiotensin products, and novel compounds that may act similarly, to improve vascular tone and reverse cardiovascular disease in the elderly, hypertensive population.Read moreRead less
Molecular And Cellular Basis For The Analgesic Properties Of N-Arachidonyl Amino Acids
Funder
National Health and Medical Research Council
Funding Amount
$509,017.00
Summary
Chronic pain affects 20% of the population of Australia, but current treatments for chronic pain are often problematic. A recently described class of compounds, the arachidonyl amino acids, show particular promise as analgesic agents, but at present there is very little understanding of how these compounds mediate their analgesic effects. In this project we will apply a variety of molecular, cellular and behavioural approaches to understand how the arachidonyl amino acids provide pain relief.
Protease-activated Receptors As Potential Drug Targets In Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Asthma is a lung disease that kills about 700 Australians each year and causes widespread morbidity in our community. For people with allergic asthma inhalation of allergens such as those contained in house dust triggers an immune response that causes swelling of the airway wall, overproduction of mucus and bronchial smooth muscle contraction. These effects lead to the narrowing of the airways that makes breathing more difficult in people with asthma. Our research groups have been investigating ....Asthma is a lung disease that kills about 700 Australians each year and causes widespread morbidity in our community. For people with allergic asthma inhalation of allergens such as those contained in house dust triggers an immune response that causes swelling of the airway wall, overproduction of mucus and bronchial smooth muscle contraction. These effects lead to the narrowing of the airways that makes breathing more difficult in people with asthma. Our research groups have been investigating a novel group of proteins, called protease-activated receptors (PARs), and in an exciting development have found that substances that stimulate PARs inhibit allergic airways inflammation in mice, which is a well-established animal model of allergic asthma. This raises the possibility that PAR stimulants may in the future be developed as anti-asthma drugs. However, there are many large gaps in our understanding of airway PARs that need to be filled before their use as anti-asthma drugs can be contemplated. Thus, the current study will address many important questions: Do PAR stimulants always improve allergic inflammation, or are there some doses or times of dosing that worsen allergic inflammation? Stimulants of one PAR, called PAR2, improve allergic inflammation, but what about stimulants of the three other PARs (PAR1, PAR3 and PAR4) that exist in the airways? How do PARs improve allergic inflammation, and which substances and cells are involved? Are PAR stimulants also effective in more complex animal models of allergic inflammation, such as those involving proteolytic allergens (e.g. Der p1 from the house dust mite), respiratory tract viruses, and extended periods of allergen exposure (chronic models) that better reflect the human disease allergic asthma? The answers to these and a range of other questions will significantly improve our understanding of the potential utility of PAR stimulants in the treatment of allergic airways disease.Read moreRead less
Substances that enhance the action of the inhibitory neurotransmitter GABA in the brain are amongst the most widely used drugs. They include many anaesthetics, anxiolytics and sedatives. Their enhancing action is mediated by increasing the effectiveness of GABA acting on GABA receptors, in particular the subtype of GABA receptors known as GABA-A receptors. This action, termed positive modulation, is poorly understood in molecular terms. Our discovery of second order modulators that only act in c ....Substances that enhance the action of the inhibitory neurotransmitter GABA in the brain are amongst the most widely used drugs. They include many anaesthetics, anxiolytics and sedatives. Their enhancing action is mediated by increasing the effectiveness of GABA acting on GABA receptors, in particular the subtype of GABA receptors known as GABA-A receptors. This action, termed positive modulation, is poorly understood in molecular terms. Our discovery of second order modulators that only act in conjunction with first order modulators adds an exciting new dimension to the concept of influencing the ways in which GABA receptors can be modulated. This offers a new approach to the development of therapeutic agents acting on GABA receptors and thus the treatement of important disorders such as anxiety, epilepsy and insomnia.Read moreRead less
Anti-atherosclerotic Effects Of Angiotensin Fragments & Non-AT1 Receptors: Validation As Innovative Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the horm ....In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the hormone, angiotensin II. Angiotensin II has been found to trigger many factors that cause thickening of the vessel wall, inflammation and imbalances in vasodilator capacity (e.g. oxidative stress and endothelial dysfunction), all of which contribute to atherosclerosis. Clinical trials with drugs that inhibit the formation of angiotensin II (ACE inhibitors), or block the action of angiotensin II (angiotensin receptor antagonists), have demonstrated a significant decrease in mortality in patients with high risk for cardiovascular disease. However their mechanism(s) of action are not fully understood as the circulating levels of shorter fragments of angiotensin II (such as Ang IV and Ang (1-7)) are raised in the blood when these drugs are used and may contribute to the protective effects of these drugs. Importantly, we have found that both Ang IV and Ang (1-7) have protective effects in atherosclerotic blood vessels. Therefore, we hypothesise that fragments of angiotensin II (such as Ang IV and others) exert anti-atherogenic effects via distinct binding sites that oppose the effects caused by angiotensin II, and that these may be partly responsible for the cardio-protective effects of the ACE inhibitors and angiotensin receptor antagonists. Thus, information gained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for the management of atherosclerosis.Read moreRead less