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Receptors form a basic intermediary as the acceptor site for signals that are transmitted between the cells that make up our body. Modulation of receptors, therefore, forms a key target in our ability to treat disease. The largest class of receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of the entire repertoire of human genes. One group of GPCRs provide the target for small prote ....Receptors form a basic intermediary as the acceptor site for signals that are transmitted between the cells that make up our body. Modulation of receptors, therefore, forms a key target in our ability to treat disease. The largest class of receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of the entire repertoire of human genes. One group of GPCRs provide the target for small protein molecules that circulate through the body. One such circulating molecule is calcitonin, a peptide that plays an important role in maintaining circulating calcium levels in the body, which is essential for proper maintenance of the skeleton. As a consequence of this action, calcitonin is an important clinically used tool in the treatment of bone disease such as osteoporosis and Paget's disease. Due to the molecular nature of calcitonin and its receptor (and other related receptors) that have a broad, complex mechanism of interaction, we have very little definitive information on how calcitonin interfaces with its receptor to signal to target cells. The current project utilises a novel method of permanently linking calcitonin to its receptor, allowing identification of how the two components come together. This information provides important fundamentals for understanding how this and related receptors work and the potential for rational design of improved therapeutic tools.Read moreRead less
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. It is extremely important to unravel how each of these components, the stimulating agent, the receptor and G protein, works in order to understand how the cells respond to various chemical signals. To make this process even more complex, it was recently shown that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play a critical role in some systems. Understanding what actually is the role of these new players, and how they team-up with the other components to elicit a specific response to a chemical stimulus, forms the basis of this proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health, abnormalities that lead to disease, and in the development of new treatments.Read moreRead less
Breast cancer remains the major form of cancer diagnosed in women, and is still the leading cause of cancer death. There remains a pressing need to find better ways to treat this disease. Increasingly, cancer treatments will make use of a growing knowledge of the factors that normally regulate cell growth, and will apply this knowledge to make cancer cells more sensitive to existing anticancer treatments. We are proposing here to study the hormone calcitonin as a novel regulator of cancer cell g ....Breast cancer remains the major form of cancer diagnosed in women, and is still the leading cause of cancer death. There remains a pressing need to find better ways to treat this disease. Increasingly, cancer treatments will make use of a growing knowledge of the factors that normally regulate cell growth, and will apply this knowledge to make cancer cells more sensitive to existing anticancer treatments. We are proposing here to study the hormone calcitonin as a novel regulator of cancer cell growth. Calcitonin is better known as a hormone that inhibits bone loss, by acting on bone resorbing cells called osteoclasts. However, our present proposal is based on our recent finding that the receptor for calcitonin is for some reason also found in many breast cancers. Moreover, we have shown that calcitonin can potently inhibit the growth of cells that have the calcitonin receptor on their surface. We plan to extend these findings in 4 ways: 1 We will make use of a large bank of breast cancer samples at the Royal Adelaide Hospital to determine whether the presence of the calcitonin receptor in breast cancers is related to other features of the tumours, such as their propensity to spread to other organs. 2 We will investigate the mechanisms by which calcitonin slows the growth of cells. 3 We have unique access to new calcitonin-like molecules, called calcitonin mimetics, which we will investigate for the ability to inhibit cell growth. These molecules are much cheaper and probably easier to administer than calcitonin itself. 4 We will investigate whether treatment of cells with calcitonin makes them more sensitive to other anticancer treatments. We hope that success in this project will lead to a more detailed understanding of the way that molecules like calcitonin can regulate cell growth and to new treatment options for cancer.Read moreRead less
Molecular Determinants Of Amino Acid-dependent Signalling By The Calcium-sensing Receptor
Funder
National Health and Medical Research Council
Funding Amount
$566,035.00
Summary
Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat. Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for tightly regulating cellular responses depending upon their levels in b ....Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat. Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for tightly regulating cellular responses depending upon their levels in blood. Identifying amino acid sensing molecules and identifying the mechanisms they use to control cellular responses is thus a key issue in human biology. The applicant identified the calcium-sensing receptor as an amino acid sensor and has shown that this receptor provides a means by which fluctuations in amino acid levels regulate the secretion of the key calcium-regulating hormone, PTH. In the current proposal, the mechanisms that link amino acid activation of the calcium-sensing receptor to its key cellular responses will be determined.Read moreRead less
Analysis Of Calcitonin Receptor Binding And Function
Funder
National Health and Medical Research Council
Funding Amount
$382,821.00
Summary
Receptors form a basic intermediary as the acceptor site for signals that are transmitted between the cells that make up our body. Modulation of receptors, therefore, forms a key target in our ability to treat disease. The largest class of receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of the entire repertoire of human genes. One group of GPCRs provide the target for small prote ....Receptors form a basic intermediary as the acceptor site for signals that are transmitted between the cells that make up our body. Modulation of receptors, therefore, forms a key target in our ability to treat disease. The largest class of receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of the entire repertoire of human genes. One group of GPCRs provide the target for small protein molecules that cirulate through the body. One such circulating molecule is calcitonin, a peptide that plays an important role in maintaining circulating calcium levels in the body, which is essential for proper maintenance of the skeleton. As a consequence of this action, calcitonin is an important clinically used tool in the treatment of bone disease such as osteoporosis and Paget's disease. Due to the molecular nature of calcitonin and its receptors (and other related receptors) that have a broad, complex mechanism of interaction, we have very little definitive information on how calcitonin interfaces with its receptor to signal to target cells. The current project utilises a novel method of permanently linking calcitonin to its receptor, allowing identification of how the two components come together. Furthermore, the project will explore the functional consequence of naturally occuring genetic variation (genotype) and also examine whether the occurence of specific calcitonin receptor genotype is correlated with disease markers for osteoporosis and obesity. This information provides important fundamentals for understanding how this and related receptors work and the potential for rational design of improved theraupeutic tools.Read moreRead less
Molecular Pharmacology Of Receptor Activity Modifying Protein (RAMP) Action
Funder
National Health and Medical Research Council
Funding Amount
$542,012.00
Summary
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore, extremely important to unravel how each of these components works. To make this process even more complex, it was recently shown that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play a critical role in some systems. We have shown that RAMPs interact with many G protein-coupled receptors and that they have a wider range of actions than has previously been appreciated. Moreover, it has been shown that the RAMP-receptor interface is a viable target for drug development. Understanding the extent to which RAMPs interact with G protein-coupled receptors, how they interact with the receptors and the consequences of this interaction forms the basis of the current proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health, abnormalities that lead to disease, and in the development of new treatments.Read moreRead less