Allosteric Modulation Of G Protein-Coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$363,000.00
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 chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aber ....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 chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aberrations in the normal function of these G protein-coupled receptors 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 G protein-coupled receptors 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 G protein-coupled receptors 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
Opioids are the most important drugs used to treat moderate to severe pain, however the development of tolerance limits their usefulness. In addition, clinically important pain states, particularly neuropathic pain, are insensitive to opioid treatment. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabinoids also have analgesic, or pain relieving properties. Of particular interest is the finding that cannabinoids enhan ....Opioids are the most important drugs used to treat moderate to severe pain, however the development of tolerance limits their usefulness. In addition, clinically important pain states, particularly neuropathic pain, are insensitive to opioid treatment. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabinoids also have analgesic, or pain relieving properties. Of particular interest is the finding that cannabinoids enhance the analgesic actions of opioids. Several brain regions are known to play a pivotal role in the analgesic actions of both opioids and cannabinoids. In previous studies I have identified the cellular and molecular mechanisms by which opioid drugs produce their analgesic effects in single brain cells. However, the cellular mechanisms underlying cannabinoid induced analgesia within the brain are poorly understood. In addition, the cellular actions of cannabinoids and opioids in neuropathic pain states are unknown. The proposed study will determine the cellular and molecular mechanisms underlying the analgesic actions of cannabinoids and opioids in single brain neurons in normal and neuropathic pain states. These techniques have the potential to identify antinociceptive combinations between cannabinoids and other agents with enhanced efficacy and reduced side effects.Read moreRead less
Mechanisms Of Action Of Neurochemicals And Modulators In Human Intestine: Changes In Disease
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Inflammatory bowel disease (IBD) and idiopathic chronic constipation (ICC) are two serious gastrointestinal disorders, for which no effective medical treatment is known. We will investigate the hypothesis that abnormalities in the nerve chemicals found in the gut contribute to the aetiology of these diseases. Our studies will examine the sites of action (receptors) for these chemicals (neurotensin and acetylcholine) in the small and large intestine. The mechanisms governing motility changes in r ....Inflammatory bowel disease (IBD) and idiopathic chronic constipation (ICC) are two serious gastrointestinal disorders, for which no effective medical treatment is known. We will investigate the hypothesis that abnormalities in the nerve chemicals found in the gut contribute to the aetiology of these diseases. Our studies will examine the sites of action (receptors) for these chemicals (neurotensin and acetylcholine) in the small and large intestine. The mechanisms governing motility changes in response to these chemicals have been well studied in animal intestine, but there is little detailed information from the human intestine. This study will provide insight into the mechanisms operating in the normal bowel, providing a base for comparing bowel obtained from patients with IBD or ICC. We will also study bowel removed at surgery for acute diverticular disease (DD), representing another type of inflammation. Studies on isolated segments of colon from ICC patients will determine whether the contractility of the muscle is abnormal in general or only with respect to the chemicals under investigation. Other studies will investigate the inflammatory processes occurring in the bowel and whether this differs in IBD. Our work will facilitate understanding of the function of the bowel in health and in gastrointestinal disorders and may lead to new medical treatments for IBD and ICC.Read moreRead less
Muscarinic Receptor Signalling, Transglutaminase And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$518,210.00
Summary
Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of di ....Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of diabetes.Read moreRead less
Cortictropin Releasing Factor As A Therapeutic Target For Alcohol And Drug Abuse
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
A key problem with alcoholism, as with addiction generally, is the chronically relapsing nature of the disorder. This can be modelled in rodents and there is good general correspondence between animal studies of reinstatement and human experience of relapse. We have identified brain chemicals involved in this process. Consequently, by better understanding the biological mechanisms related to addiction and relapse, we will be in a position to counter this devastating condition.
Influence Of Endothelin And Protease-activated Receptors On Eosinophil Trafficking In The Airways Of Allergic Mice
Funder
National Health and Medical Research Council
Funding Amount
$376,980.00
Summary
Asthma is a chronic inflammatory lung disease. This disease affects about 10% of the population, although its incidence in primary school-age children is as high as 30% in some cities. People suffering from asthma have very responsive (hyperresponsive) airways to substances which are usually innocuous. Many asthmatics are allergic to substances such as pollens, animal dander and house dust, which causes the airways of the asthma sufferer narrow, making breathing more difficult. The airways of as ....Asthma is a chronic inflammatory lung disease. This disease affects about 10% of the population, although its incidence in primary school-age children is as high as 30% in some cities. People suffering from asthma have very responsive (hyperresponsive) airways to substances which are usually innocuous. Many asthmatics are allergic to substances such as pollens, animal dander and house dust, which causes the airways of the asthma sufferer narrow, making breathing more difficult. The airways of asthma sufferers also become inflamed and the resulting swelling of the airways and excess formation of mucous makes breathing difficult. Inflamed asthmatic airways contain large numbers of cells called eosinophils, which move from the blood into the airways. Substances released from the eosinophils are thought to damage the airways and cause airways hyperresponsiveness. We have developed a mouse model of allergic inflammation which has many of the hallmark features of asthma, including high numbers of eosinophils and hyperresponsive airways. We have recently shown that these effects are inhibited by treatment of allergic mice with a drug called SB217242. SB217242 inhibits the actions of endothelin, a peptide that is produced in elevated amounts in the airways of asthma sufferers and which may produce many of the effects associated with asthma. We wish to investigate the mechanisms through which SB217242 and drugs which stimulate novel protease-activated receptors inhibits the increase in eosinophil numbers in the airways. We will investigate the possibility that these drugs inhibit the migration of eosinophils from the blood into the airways, using a unique microscope that allows us to visualize the movement of eosinophils into tissues such as the airways. These studies are likely to be of considerable strategic value in determining the potential usefulness of these drugs in the treatment of asthma.Read moreRead less
Flavonoids are widely consumed in the diet in food, beverages and herbal preparations. They have diverse actions on the body. We wish to investigate how they might affect brain function. One of the most important transmitters in the brain is a chemical known as GABA. Many known CNS drugs, such as alcohol and the benzodiazepine Valium, influence the action of GABA as a transmitter. These drugs enhance the action of GABA in activating particular receptors in the brain. We have discovered that apig ....Flavonoids are widely consumed in the diet in food, beverages and herbal preparations. They have diverse actions on the body. We wish to investigate how they might affect brain function. One of the most important transmitters in the brain is a chemical known as GABA. Many known CNS drugs, such as alcohol and the benzodiazepine Valium, influence the action of GABA as a transmitter. These drugs enhance the action of GABA in activating particular receptors in the brain. We have discovered that apigenin, a flavonoid found in many herbal preparations and in beverages such as camomile tea, has a special action on GABA in that it enhances the enhancing action of benzodiazepines on GABA receptors. This is a novel mode of drug action that needs to be explored further. We will study the actions of a range of flavonoids known to occur in various popular products such as soy milk, red wine and green tea for their effects on GABA receptors. From the results we plan to design and synthesise new substances with a view to discovering new therapeutic agents to treat a range of CNS disorders, such as anxiety, epilepsy and memory deficits. This project will also yield information on the possible interactions between alcohol and prescription drugs like Valium with flavonoids consumed in the diet. Already it is known that a flavonoid in grape fruit juice may influence the metabolism of drugs like Valium. This project will be concerned with possible interactions within the brain. The novel mode of action that we have discovered is of significance in terms of our basic understanding of brain function. It could add another dimension to what we already know about the brain as our most complex organ.Read moreRead less