LRH-1 is a protein that is inappropriately present in cancers of the breast and other tissues. It causes cancer cells to divide and multiply, and therefore it is important to block its activity. There are, however, no treatments available that block LRH-1. This proposal brings together a team of researchers with broad experience. We will use high throughput technologies to identify and characterize novel LRH-1 inhibitors, and demonstrate their efficacy in reducing the growth of cancer cells.
Protein / Protein Interactions Important For AMP-activated Protein Kinase Regulation
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
The AMP-activated protein kinase (AMPK) is an enzyme that monitors the energy levels of the body. When oxygen and nutrient levels decrease, the energy levels of a cell also decrease leading to activation of the AMPK. This results in activation of energy-producing pathways and inhibition of energy-consuming pathways, allowing cells to match supply with demand to ensure their survival. The AMPK comprises of three proteins that together form a functional enzyme. In this application I aim to obtain ....The AMP-activated protein kinase (AMPK) is an enzyme that monitors the energy levels of the body. When oxygen and nutrient levels decrease, the energy levels of a cell also decrease leading to activation of the AMPK. This results in activation of energy-producing pathways and inhibition of energy-consuming pathways, allowing cells to match supply with demand to ensure their survival. The AMPK comprises of three proteins that together form a functional enzyme. In this application I aim to obtain a thorough understanding of the molecular basis of how the AMPK functions. I will determine how and where the three proteins interact with each other and determine where in a cell at any given time the AMPK can be found. This is an important question to answer because many proteins are inactive within the cytoplasm but when they are bound to the plasma membrane they are active. I have previously found the AMPK to be localized to the cytoplasm, membrane and nuclear compartments of the cell, but little is known about the AMPK s function in these different locations. Activation of the AMPK is known to depend on another protein that is also activated when cellular energy levels decrease. This protein has remained elusive to many researchers over the past few years. I plan to identify this protein using new bioinformatics together with the vast amount of information provided by the sequencing of the human genome. Exercise and reduced caloric intake activate the AMPK, these are associated with health benefits and reduce the risk of cardiovascular and neurodegenerative diseases, diabetes and obesity. For these reasons information on the role of the AMPK may improve our understanding of the reasons these diseases develop.Read moreRead less
Regulation And Functional Roles Of ADAM 10 Protease In Prostate Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cel ....Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cells to break free from their original tissue positions, walk through surrounding tissue and deposit themselves at distant sites to form a secondary tumour. In this research we are looking at a protein, called ADAM-10, which belongs to a family of proteases, the ADAMs, which contain both A Disintegrin And Metalloprotease activity, hence their name. Our data suggest ADAM-10 is produced in large quantities by prostate cancer cells but can be differently located within these cells it sits on the outer membrane of normal or benign prostate glands but re-locates to the cell nucleus in high grade prostate cancer cells. We have also identified ADAM-10 protein in small membrane fragments that are commonly shed from prostate cancer cells. Preliminary evidence suggests that levels of ADAM-10 in each of these locations is regulated by growth factors and-or the male sex hormone, androgen, key hormones involved in prostate cancer growth and progression. We do not yet know what actions ADAM-10 has when it occurs in these different locations but believe the membrane form will be involved in metastasis, with the nuclear form being involved in regulating events within the nucleus, the control centre for the cell. This grant application aims to build on our novel observations and investigate the underlying mechanisms of ADAM-10 hormonal regulation and function. If proven, these issues may be important for the development, progression and future treatment of prostate cancer.Read moreRead less
Negative Regulators Of Nuclear Import; Potential Links To Cancer
Funder
National Health and Medical Research Council
Funding Amount
$495,829.00
Summary
Trafficking of proteins into the nucleus is critical to mammalian cell function, relating strongly to developmental processes and cancer. We have identified a new class of molecule - negative regulators of nuclear import - that function to prevent entry into the nucleus of key regulators of the cell cycle-apoptosis, and have a potential link thereby to cancer. We propose to determine their mechanism of action, modulation by cellular signals, and how important this is to cell function-cancer.
Structure-function Analysis Of Nuclear Receptor And Cofactor Action: Evidence For A Role In Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a pr ....Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a previously unknown hormone, and metabolic pathway. We are interested in the orphan hormone receptors, Rev-erbA and RVR, orphan members of the receptor superfamily. Rev-erb alpha expression is regulated by fibrates, widely used hypolipidemic drugs, and the circadian cycle. Rev-erbs mediate the regulation of lipid metabolism and peroxisomal beta oxidation. Furthermore, Rev-erbs are acutely induced during brain seizures, postulated to regulate cerebellar plasticity, and involved in growth control. In view of these critical regulatory roles, and the success of reverse endocrinology to date, we intend to complete the structural analysis of the Rev-erb and RVR as a tool to identify the hormone that binds this receptor. Hormone receptors recruit proteins called nuclear receptor cofactors, that function as regulators of gene expression. The cofactors regulate gene expression and development. Furthermore these cofactors, when misregulated result in the onset of disease and carcinogenesis, which underscores the need for achieving a high resolution view of their function in many tissues. Along these lines, we are interested in exmining the function of these cofactors in muscle. Understanding the molecular role of the NR cofactors during muscle differentiation will be a critical step toward elucidating the dysregulation-function of these proteins in muscle diseases, such as rhabdomyosarcoma and inflammatory myopathy that have cofactor deficiency.Read moreRead less
The Interactions Of Dengue Virus RNA Dependent RNA Polymerase (NS5) With Other Viral And Host Factors.
Funder
National Health and Medical Research Council
Funding Amount
$170,165.00
Summary
Dengue fever is a mosquito-borne disease that is prevalent in tropical countries. It is estimated that 40% of the global population is at risk of dengue infection. Classical dengue fever is not life threatening. However, the more serious disease, dengue haemorrhagic fever-shock syndrome requires intensive medical attention to prevent fatality. A significant number of deaths are recorded each year especially in the underdeveloped countries. Dengue is periodically also a problem in northern Austra ....Dengue fever is a mosquito-borne disease that is prevalent in tropical countries. It is estimated that 40% of the global population is at risk of dengue infection. Classical dengue fever is not life threatening. However, the more serious disease, dengue haemorrhagic fever-shock syndrome requires intensive medical attention to prevent fatality. A significant number of deaths are recorded each year especially in the underdeveloped countries. Dengue is periodically also a problem in northern Australia. There is no cure for dengue fever. The present research aims to use a knowledge-based approach to develop novel antiviral strategies based on preventing the critical protein interactions required for the normal virus life cycle. Two of the most important proteins involved in dengue virus replication are called the NS3 and NS5 proteins. The protein-protein interaction (contact) that occurs between NS5 and NS3 is crucial for the replication of the virus. Little is known about this interaction at present, and the studies we propose will directly address this issue. We have previously shown that a 37 amino acid in the middle of NS5 contains a nuclear localisation signal that can target the normally cytoplasmic protein to the nucleus of the infected cell. What the function of this protein is in the nucleus is not known. We will use a technique called the yeast two-hybrid test to address the question of dengue virus protein interactions in the common bakers yeast. This method is very sensitive and powerful and will provide important insights that will contribute to the development of a rapid high-throughput test to screen the extensive extract collection from Australia's marine biodiversity, held by the Australian Institute of Marine Sciences, to discover suitable inhibitors of NS3-NS5 interaction.Read moreRead less
Regulation Of Subcellular Localisation Of Respiratory Syncytial Virus M Protein: Implications For Pathology
Funder
National Health and Medical Research Council
Funding Amount
$580,195.00
Summary
Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and the elderly, causing more deaths in winter than influenza. We have observed RSV M protein in the nucleus of infected host cells where it inhibits host cell transcription. We propose to investigate the regulation of nuclear localisation of M by phosphorylation and binding to cellular factors and its importance to RSV pathogenesis. The results will relate strongly to future drug and vaccine development.
A New Approach to the Structure of Atomic Nuclei. Starting at the quark level, we have derived a theory of nuclear structure, that in its initial application appears extremely successful. The aim of this project is to advance this revolutionary new approach to the theory of nuclear structure to the next level by exploring its predictions for a number of outstanding questions in modern nuclear physics. This includes the properties of superheavy nuclei, with atomic number beyond 100, including the ....A New Approach to the Structure of Atomic Nuclei. Starting at the quark level, we have derived a theory of nuclear structure, that in its initial application appears extremely successful. The aim of this project is to advance this revolutionary new approach to the theory of nuclear structure to the next level by exploring its predictions for a number of outstanding questions in modern nuclear physics. This includes the properties of superheavy nuclei, with atomic number beyond 100, including the potential existence of a new region of stability and complementing experimental searches underway internationally to discover the limits of stability with large neutron or proton excess, which is crucial to understanding the origin of the elements and may contribute new energy related technology.Read moreRead less