Pharmacology Of Potential Anti-Tumour Agents: Iron Chelators Of The BpT Class
Funder
National Health and Medical Research Council
Funding Amount
$585,455.00
Summary
Pharmacology of Potential Anti-Tumour Agents: Iron Chelators of the BpT Class Cancer cells have a high iron requirement for DNA synthesis and many clinical trials showed Fe chelators are effective anti-cancer drugs. Their potential to act as anti-tumour agents has been confirmed by the entrance of Triapine into widespread NCI clinical trials. In this NHMRC Renewal, we will perform pharmacological and preclinical studies to promote the development of BpT chelators as novel anti-tumour agents.
Pharmacological Targeting Via AKT, PTEN, And TGF-beta Pathway Integration Using Novel Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$634,875.00
Summary
We have identified potentially important interactions of cellular pathways that vary between individual sufferers, but which also provide common molecular targets for novel drug development. Our suite of novel and potent drugs that markedly and selectively inhibit cancer cell growth will be studied to determine if these pharmaceutical agents act to inhibit tumour cell proliferation by targeting common effector molecules of integrated cellular pathways.
Factors Regulating The Temporal And Spatial Assembly Of G-protein Coupled Receptor-mediated Arrestin Complexes
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
G-protein coupled receptors are proteins that are present at the surface of most cells in the human body. They recognise and bind to specific molecules, such as hormones, the act of which results in a specific signal being transmitted into the cell. This signal alters the function of the cell and so it is critical that it is appropriate, both in type and duration. G-protein coupled receptors and the molecules that activate them provide an essential function within the human body for communicatin ....G-protein coupled receptors are proteins that are present at the surface of most cells in the human body. They recognise and bind to specific molecules, such as hormones, the act of which results in a specific signal being transmitted into the cell. This signal alters the function of the cell and so it is critical that it is appropriate, both in type and duration. G-protein coupled receptors and the molecules that activate them provide an essential function within the human body for communicating between cells, and consequently between organs. They are a major mechanism by which nerve signals are transmitted and hormones regulate bodily functions. They are therefore an important target for pharmaceuticals, with up to 50% of ethical drugs and many drugs of abuse acting upon them. It is critical to understand how these receptors alter cellular function once they receive an appropriate signal, but it is also essential to know how such responses are switched off. Arrestins are proteins within cells that interact with G-protein coupled receptors to 'arrest' their signalling. They desensitise the cell to continuous stimulation, but also act to resensitise the cell to respond to future, separate signals. Recently, they have also been shown to provide alternative mechanisms of altering cellular activity by interacting with other cellular proteins. These interactions greatly increase the potential ways in which a cell can respond once a G-protein coupled receptor is activated. Understanding the resulting complexity is essential if we are to fully exploit the vast therapeutic potential of this important receptor family.Read moreRead less
Novel Interactions Between GnRH Receptor And E2F4 Transcription Factor.
Funder
National Health and Medical Research Council
Funding Amount
$462,750.00
Summary
The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reducti ....The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reduction of gonadotropin secretion and consequent decline in steroid production. As the majority of tumours treated with GnRH analogues are hormone-dependent, this starves the tumour of the steroid support required for growth. However, the concept of a direct anti-tumour effect of GnRH, independent of the pituitary-gonadal axis, is supported by the in vitro inhibition of both cell growth and DNA synthesis in a number of tumour cell lines. Despite the wide use of GnRH analogues, the molecular basis of the growth inhibitory effects resulting from the activation of this receptor is not fully understood. Unravelling the protein interactions underlying receptor-mediated signalling events will provide valuable information towards understanding of receptor function in vivo. We have identified a novel interaction involving the GnRHR and E2F4, a transcription factor involved in suppression of the transcription of genes involved in cell cycle progression. In addition, over 80% of E2F4 knockout mice are sterile. Owing to the role of the GnRHR in the reproductive pathway we are interested in determining whether the GnRHR-E2F4 interaction has an influence on the development of the hypothalamic-pituitary-gonadal axis, hence affecting reproductive capacity. The interaction identified and studied in this proposal has implications for the treatment of reproductive tumours, such as those of the breast and prostate, and understanding the development of the hypothalamic-pituitary-gonadal axis.Read moreRead less
Deconstructing DTCA: Towards A Differentiated Policy Response To Direct-to-Consumer Advertising In Australia.
Funder
National Health and Medical Research Council
Funding Amount
$190,760.00
Summary
Spending on prescription pharmaceuticals is the fastest growing part of the health budget. In recent years attention has shifted to the impact of direct-to-consumer advertising (DTCA) on consumer demand and drug costs. Although DTCA is prohibited in Australia, it is clear that different types of DTCA are occurring. This study will examine the nature and range of DTCA, review the benefits and harms of DTCA, and identify the perspectives of major stakeholders regarding DTCA. The study will culmina ....Spending on prescription pharmaceuticals is the fastest growing part of the health budget. In recent years attention has shifted to the impact of direct-to-consumer advertising (DTCA) on consumer demand and drug costs. Although DTCA is prohibited in Australia, it is clear that different types of DTCA are occurring. This study will examine the nature and range of DTCA, review the benefits and harms of DTCA, and identify the perspectives of major stakeholders regarding DTCA. The study will culminate in a national workshop which will develop a differentiated set of recommendations for responding to different types and modes of DTCA. This is likely to lead to better health policy and to resources that may assist consumers and health professionals deal with DTCA.Read moreRead less
Many products are applied to the skin to prevent skin cancer or to treat skin diseases. This project seeks to better understand how we can make such products more affective, safer and appropriate for conditions such as psoriasis. One major component of the grant is concerned with the evaluation of nanotechnology products applied to the skin.
Novel G-protein Coupled Receptor Interactions And Complexes With Distinct Function And Pharmacology
Funder
National Health and Medical Research Council
Funding Amount
$246,760.00
Summary
G protein coupled receptors (GPCRs) are the target in the human body for most of today's medicines. Almost all pharmaceutical companies market drugs that are GPCR agonists or antagonists aimed at diverse disease states. Our research is focused on the molecular basis of drug recognition and signalling by GPCRs. We use genetic engineering techniques to create new receptors and mutant receptors in order to identify the functional domains of these signalling molecules. We have recently established a ....G protein coupled receptors (GPCRs) are the target in the human body for most of today's medicines. Almost all pharmaceutical companies market drugs that are GPCR agonists or antagonists aimed at diverse disease states. Our research is focused on the molecular basis of drug recognition and signalling by GPCRs. We use genetic engineering techniques to create new receptors and mutant receptors in order to identify the functional domains of these signalling molecules. We have recently established a novel approach based on proximity-dependent fluorescent technologies to explore receptor interactions and have described the formation of functional G-protein coupled complexes in living cells. This project is to discover new receptor combinations which could potentially affect signalling pathways and redirect cellular responses. Investigation of the mechanisms involved in turning on and off the body s response to stimuli would provide valuable information for drug design and treatment of GPCR-related conditions. We have chosen to use two GPCRs as models for our study of the mechanisms controlling receptor driven cellular responses and the interactions between cellular components-proteins behind this control. Firstly, the gonadotropin releasing hormone receptor (GnRHR), a protein located in the pituitary which is pivotal in the control of reproduction and secondly, the thyrotropin releasing hormone receptor (TRHR), similarly located and involved in modulating thyroid and metabolic function. We will investigate the way these receptors interact with other cellular proteins in order for them to function. Ultimately this will provide a better understanding of how these clinically important proteins function and pave the way for the development of clinical applications that target these receptor systems, resulting in the effective treatment of a wide range of conditions and diseases, including pain, migraine, certain forms of cancer, neurological and reproductive disorders.Read moreRead less
Within the nervous system, neurons communicate through the release of neurotransmitter chemicals across connections between individual neurons (synapses). Before their release, neurotransmitters are stored inside nerve endings, within small membranous spheres called synaptic vesicles. Neuronal cell shape and the neuron's ability to migrate to different regions of the brain during development affect the way that the adult brain functions. Alterations in any of these brain functions may lead to di ....Within the nervous system, neurons communicate through the release of neurotransmitter chemicals across connections between individual neurons (synapses). Before their release, neurotransmitters are stored inside nerve endings, within small membranous spheres called synaptic vesicles. Neuronal cell shape and the neuron's ability to migrate to different regions of the brain during development affect the way that the adult brain functions. Alterations in any of these brain functions may lead to diseases affecting normal mental function. Ral is a small GTPase enzyme found in brain, and particularly in neurons. Small GTPases are responsible for regulating cell functions by acting as switches, turning biochemical processes on and off inside the cell. Within neurons, Ral is found on the surface of synaptic vesicles, implicating it in the regulation of neurotransmitter release. Other Ral functions have been demonstrated in non-neuronal cells that may be of particular significance in neuronal cells. However, no studies have previously investigated Ral function in the nervous system. The research proposed aims to establish what role RalA performs within neuronal cells, and by what biochemical mechanism it performs this role. Techniques of molecular biology, biochemistry and microscopy will be used to establish these functions. This research will lead to increased knowledge of the significance of this protein to cellular, and particularly neuronal cell function. This forms the basis for the understanding normal neuronal function, and for the identification of factors causing diseases of the nervous system. In time, such research aids in the development of specific therapies for sufferers of such diseases of the nervous system.Read moreRead less
A Novel Tumour-targeting Nanoliposome Drug Delivery System For The Treatment Of Malignant Gliomas
Funder
National Health and Medical Research Council
Funding Amount
$445,097.00
Summary
Most patients with malignant brain tumours die within a year after diagnosis due to the difficulty in effectively delivering drugs to the tumour cells. We aim to develop a safe and novel drug delivery system to effectively deliver anticancer drugs and novel anticancer agents to brain tumour cells that remain in normal brain after surgery. The success of this project will bring us a step forward in our efforts to significantly improve the survival rate and quality of life of such patients.
Recognition Of Macromolecular Complexes By Cell Surface Receptors: A Novel Mechanism Of Lipid And Drug Absorption
Funder
National Health and Medical Research Council
Funding Amount
$398,156.00
Summary
A clear understanding of the mechanisms by which orally ingested materials are absorbed from the gastrointestinal tract is critical in areas such as nutrition, drug development and toxicology. The current project aims to evaluate the role of specific receptor types in the intestine in the absorption of both dietary lipids and drug molecules, with a view to providing a means to better regulate lipid absorption and to more effectively facilitate the design of improved drug delivery systems.