Molecular Mechanisms Of G Protein-Coupled Receptor Cross Talk
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
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, such as schizophrenia, pain and dementia. To date, most therapeutic approaches to treating these disorders have targeted individual types of G protein-coupled receptors thought to play a role in each disease state, but this has met with mixed success. One of the reasons for this is that each disorder actually involves more than one type of G protein-coupled receptor communicating with other types in a complex way. Our current proposal specifically focuses on some of the newer mechanisms that have been suggested to play an important role in the communication between different types of G protein-coupled receptors located in the same type of cell. An understanding of how such receptor proteins can communicate with one another in this situation is absolutely vital in unravelling processes involved in the maintenance of health, abnormalities that lead to disease and in the development of more effective treatments.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
Alteration Of Glucose Metabolism By GPCR Activation
Funder
National Health and Medical Research Council
Funding Amount
$444,796.00
Summary
In type 2 diabetes the effect of insulin to stimulate glucose transport in fat cells and skeletal muscle is impaired so there is great interest in identifying insulin-independent mechanisms that increase glucose transport. Several G protein-coupled receptors (GPCRs) regulate glucose transport independently of insulin but the mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate glucose homeostasis and will evaluate them as potential treatments.
Targeted Cancer Chemotherapy: The Potential Of L-Nucleoside Prodrugs
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
The aim of this project to develop novel anti-cancer agents. We plan to use an unusual sugar (an L-nucleoside) that is not normally found in the body. This unusual sugar has the property of being taken up by tumour cells but not normal cells. We will use this unusual sugar to transport a toxic compound inside tumour cells so that the tumour cells are killed. In this way, we will preferentially kill tumour cells but leave normal cells unaffected. Hence we will produce an anti-cancer agent that is ....The aim of this project to develop novel anti-cancer agents. We plan to use an unusual sugar (an L-nucleoside) that is not normally found in the body. This unusual sugar has the property of being taken up by tumour cells but not normal cells. We will use this unusual sugar to transport a toxic compound inside tumour cells so that the tumour cells are killed. In this way, we will preferentially kill tumour cells but leave normal cells unaffected. Hence we will produce an anti-cancer agent that is highly effective at killing tumour cells but has few side-effects because it does not enter normal cells. Experimentally we will synthesise compounds where the L-nucleoside is attached to a toxic agent, fluorouridine or cisplatin analogues. We will then assess the ability of these novel compounds to kill tumour cells grown in the laboratory as well as tumours growing in mice. Additionally we will attempt to determine the mechanism of action of these drugs by investigating the following: the transport properties of the drugs; how and where these drugs damage DNA; the effect of the gene, p53, which can act to stop tumour growth. The ultimate aim of this project is to develop a novel class of anti-tumour agent based on L-nucleosides. These L-nucleoside analogues are expected to be more efficient at killing tumour cells but have fewer side effects.Read moreRead less
Pharmacological Modulation Of Microglial Responses After Transient Forebrain Ischaemia In Rats
Funder
National Health and Medical Research Council
Funding Amount
$170,906.00
Summary
A stroke is caused by an acute blockade of blood flow to a brain region and is normally caused by a clot in the artery that supplies blood to that region. Within minutes, the region of the brain that is receiving no blood flow, dies and so the functions controlled by that region cease. If this region controls key functions such as breathing then the patient dies and this occurs in about one third of patients. However, in the majority of patients, the blockage affects parts of the brain controlli ....A stroke is caused by an acute blockade of blood flow to a brain region and is normally caused by a clot in the artery that supplies blood to that region. Within minutes, the region of the brain that is receiving no blood flow, dies and so the functions controlled by that region cease. If this region controls key functions such as breathing then the patient dies and this occurs in about one third of patients. However, in the majority of patients, the blockage affects parts of the brain controlling movement of limbs or speech and so these patients suffer permanent disabilities. Not surprisingly, stroke is the most common life-threatening neurological disease and the major cause of disability in adults over 45. Apart from the profound effect stroke has on the patient and the family, the annual cost of disability to the Australian community is approx $ 1 billion. If the disability could be minimised by reducing institutionalization then the cost saving would be great. Research is being carried out to define how nerves die when they have insufficient blood supply and progress has been made in understanding the biochemical basis of this process. Such knowledge opens the way for the design of novel drugs to delay nerve death. Our laboratory has been successful in designing a novel drug, AM-36 that minimises nerve death in the forebrain of rats that have had the blood supply to the forebrain interrupted for 3 to 5 hours. A recent report has shown that a stroke in the forebrain can lead to nerve damage in the spinal cord and this could contribute to impaired walking in stroke patients. This is an unexpected finding and this project seeks to define how and when nerves in the spine die after a stroke in the forebrain. Such information should then lead to the rational design of drugs to minimise the death of nerves in the spinal cord as well as in the forebrain.Read moreRead less
Understanding The Mechanisms Used By G-protein Coupled Receptors To Regulate Insulin-independent Glucose Transport
Funder
National Health and Medical Research Council
Funding Amount
$105,590.00
Summary
In type 2 diabetes, stimulation of glucose transport in fat cells and skeletal muscle by insulin is impaired. As a result there is great interest in identifying insulin-independent mechanisms that increase glucose transport. Several G-protein coupled receptors (GPCRs) regulate glucose transport independently of insulin but the mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate glucose transport for potential as treatments.