PROTEIN TARGETS FOR THE STEROID RECEPTOR MODULATOR, CYCLOPHILIN 40
Funder
National Health and Medical Research Council
Funding Amount
$374,828.00
Summary
Steroids bind to specific receptor proteins in steroid responsive cells. These receptors are kept in a steroid-binding ready state by chaperone proteins which function to fold the receptors appropriately. The major chaperone protein is heat shock protein, hsp90. A second family of proteins called immunophilins, cooperate with hsp90 in receptor folding. These immunophilins can bind to immunosuppressant drugs, which may result in a change in receptor function. We have identified one of these immun ....Steroids bind to specific receptor proteins in steroid responsive cells. These receptors are kept in a steroid-binding ready state by chaperone proteins which function to fold the receptors appropriately. The major chaperone protein is heat shock protein, hsp90. A second family of proteins called immunophilins, cooperate with hsp90 in receptor folding. These immunophilins can bind to immunosuppressant drugs, which may result in a change in receptor function. We have identified one of these immunophilins as cyclophilin 40 ( CyP40), a protein that binds the immunosupressant drug, cyclosporin A. We have recently found that, in addition to binding to hsp90, CyP40 may bind to and regulate the function of other proteins which are important in how cells grow and die. The aims of this project are to study how CyP40 binds to hsp90 and to these other proteins and to determine the functional outcomes of these interactions.Read moreRead less
The Role Of Steatosis In Promoting Cellular Injury And Fibrogenesis In Human Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$414,375.00
Summary
Lay Description Fatty liver (steatosis) is important because it increases the vulnerability of the liver to factors that trigger inflammation and fibrosis. Patients with steatosis may develop steatohepatitis spontaneously and this increases the risk and rate of progression to cirrhosis, with consequent liver-related morbidity and mortality. In addition, steatosis significantly potentiates the severity of liver damage that is caused by other agents such as drugs or infections. To improve the prog ....Lay Description Fatty liver (steatosis) is important because it increases the vulnerability of the liver to factors that trigger inflammation and fibrosis. Patients with steatosis may develop steatohepatitis spontaneously and this increases the risk and rate of progression to cirrhosis, with consequent liver-related morbidity and mortality. In addition, steatosis significantly potentiates the severity of liver damage that is caused by other agents such as drugs or infections. To improve the prognosis of patients with fatty livers, it is important to understand why hepatic steatosis increases the risk for more serious liver disease. To date, much of our understanding of mechanisms of liver injury in fatty liver disease comes from animal models, and these findings have not been systematically evaluated in the human disease. Apart from optimizing body weight, there is no established treatment of fatty liver disease. Delineation of the mechanisms involved in liver injury will allow the development of specific protective strategies for steatotic livers.Read moreRead less
Cell Cycle Regulation By The Epidermal Growth Factor Receptor
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The rate of growth and death of normal cells is regulated through signals transmitted from the cell surface to the nucleus. In many human cancers the normal regulatory mechanisms are subverted, leading to uncontrolled growth of the cells. We aim to characterize the signals that are initiated by binding of the Epidermal Growth Factor (EGF) to its receptor and to understand how these signals influence the ability of the cell to divide and to survive. We will identify the pathways that contribute t ....The rate of growth and death of normal cells is regulated through signals transmitted from the cell surface to the nucleus. In many human cancers the normal regulatory mechanisms are subverted, leading to uncontrolled growth of the cells. We aim to characterize the signals that are initiated by binding of the Epidermal Growth Factor (EGF) to its receptor and to understand how these signals influence the ability of the cell to divide and to survive. We will identify the pathways that contribute to uncontrolled growth in tumor cells. This knowledge is necessary for the design of new therapies targetted to the molecular lesions which stimulate solid tumors.Read moreRead less
CHARACTERISATION OF A NOVEL REGULATOR OF PHOSPHOINOSITIDE 3-KINASE-MEDIATED CELL PROLIFERATION AND PLATELET SIGNALLING
Funder
National Health and Medical Research Council
Funding Amount
$500,091.00
Summary
Critical functions such as cell growth, cell death and metabolism, are tightly controlled by key proteins which respond to specific stimuli. Perturbation of this process may lead to uncontrolled growth and cancer. This project proposes to examine the potential of a novel protein (an enzyme) as a physiological regulator of cell growth. It is proposed that this enzyme may function as a brake in preventing the evolution of a cancerous state. We will also study the ability of the novel enzyme to inf ....Critical functions such as cell growth, cell death and metabolism, are tightly controlled by key proteins which respond to specific stimuli. Perturbation of this process may lead to uncontrolled growth and cancer. This project proposes to examine the potential of a novel protein (an enzyme) as a physiological regulator of cell growth. It is proposed that this enzyme may function as a brake in preventing the evolution of a cancerous state. We will also study the ability of the novel enzyme to influence other diverse functions, such as uptake of glucose, and blood clot initiation.Read moreRead less
Alternative Mechanisms To Initiate Apoptotic Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$336,767.00
Summary
Cell death is essential for our well being. As insufficient cell deaths can lead to cancers, promoting cell killing is a promising new avenue for treating this disease. However, current approaches are not fully optimal because we do not completely understand how the switch for cell death is flipped on. Our project seeks to answer this important question and we anticipate that a better understanding of this basic process will enable improved treatment for diseases such as cancer.
Anti-apoptotic, Anti-fibrotic, And Positive Inotropic Effects Of Ghrelin And GHRP On Rat And Mouse Cardiac Myocytes
Funder
National Health and Medical Research Council
Funding Amount
$442,530.00
Summary
Growth hormone (GH) is a protein hormone secreted from an endocrine organ, the pituitary gland, below the brain. Synthetic GH-releasing peptides (GHRPs) and endogenous GHRP (ghrelin) possess many other physiological functions in addition to the release of GH. GHRPs have been shown to affect cardiac function in animals and humans through their specific receptors. We recently demonstrated at single cell level that GHRPs increased contraction of cardiac muscle cells and protected them from the prog ....Growth hormone (GH) is a protein hormone secreted from an endocrine organ, the pituitary gland, below the brain. Synthetic GH-releasing peptides (GHRPs) and endogenous GHRP (ghrelin) possess many other physiological functions in addition to the release of GH. GHRPs have been shown to affect cardiac function in animals and humans through their specific receptors. We recently demonstrated at single cell level that GHRPs increased contraction of cardiac muscle cells and protected them from the programmed cell death which occurs in heart failure and myocardial infarction. We also demonstrated that GHRPs protected the heart in chronic heart failure and alleviated functional loss of the heart in experimental heart failure models. Preliminary results now indicate that GHRPs prevent cardiac fibrosis, which accounts for cardiac dysfunction after heart failure and infarction. It is proposed in this project to clarify the mechanism underlying the action of GHRPs in (1) cardiac functional enhancing; (2) anti-cell death; (3) anti-fibrosis effects, in primary cultured rat myocytes in vitro and in cardiac diseased mouse models in vivo. By completing this project, we will be able to (1) better understand the physiological role of ghrelin in the regulation of cardiac function; and (2) clarify the potential for therapeutic use of GHRPs in the treatment of chronic heart failure, a disease affecting 1-2% of the population of Australia, with 5 year mortality rates about 65%.Read moreRead less
Characterisation Of The Tumour Suppressor Function Of Caspase-2
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Aberrant cell death (apoptosis) is associated with many diseases including cancer. Apoptosis is mediated by a group of enzymes called caspases. Recently we have discovered that one of these enzymes, caspase-2, acts as a tumour suppressor. We now wish to validate this finding in several preclinical models of cancer and understand precisely how caspase-2 works to safeguard cells against cancer development. These studies will help better understand cancer and ways to treat it.
Determinants Of Insulin-like Growth Factor (IGF) Binding And Biological Actions Of IGF Binding Protein-6
Funder
National Health and Medical Research Council
Funding Amount
$399,750.00
Summary
Proteins are complex structures usually consisting of a number of distinct regions. Each of these regions may serve different roles. Insulin-like growth factors (IGFs) are important proteins involved in regulating the growth and other properties of cells. The actions of IGFs are in turn regulated by a family of binding proteins (IGFBPs). The aim of this project is to determine the range of actions of one of these IGFBPs and which parts of this IGFBP are involved in these actions. This may lead t ....Proteins are complex structures usually consisting of a number of distinct regions. Each of these regions may serve different roles. Insulin-like growth factors (IGFs) are important proteins involved in regulating the growth and other properties of cells. The actions of IGFs are in turn regulated by a family of binding proteins (IGFBPs). The aim of this project is to determine the range of actions of one of these IGFBPs and which parts of this IGFBP are involved in these actions. This may lead to new treatments for diseases in which cell growth is disturbed e.g. cancer and diabetes.Read moreRead less
Examination Of The Mechanism By Which The Salvador/warts/hippo Complex Restricts Cell Growth And Number
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created r ....Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created random mutations in the vinegar fly, Drosophila, and tested their ability to cause solid cancers. Drosophila is an excellent model organism for this study because many of the pathways that are often perturbed in cancer are conserved between humans and flies. Using this approach we identified several known and novel genes that cause cancerous growths. By studying the human counterparts of these novel genes we identified a potential role for some of these genes in the generation of human cancer. Three of these genes, hippo, salvador and warts, appear to act in concert to restrict cell number. In this study we aim to understand the mechanism by which these genes restrict cell number. To do this we will analyze how the activity of this pathway is controlled and in what tissues it functions. We also plan to discover other key components of this pathway that function downstream of hippo, salvador and warts. To perform these experiments we will use a variety in vitro biochemical techniques as well as experiments in tissue culture cells. We will then verify the results of these experiments in the context of a whole animal. By performing these experiments we hope to gain greater insight into the genesis of cancer.Read moreRead less
The Role Of Melanoma Tumour Antigen P97 (Melanotransferrin) In Melanoma Tumourigenesis.
Funder
National Health and Medical Research Council
Funding Amount
$563,242.00
Summary
The Role of Melanoma Tumour Antigen p97 (Melanotransferrin) in Melanoma Tumourigenesis Melanotransferrin (MTf) is a homologue of the iron transport protein, transferrin, and was one of the first well characterised melanoma tumour antigens. Our published studies have shown that MTf plays an important role in melanoma tumourigenesis in vivo. In this proposal, we will assess if it is associated with melanoma progression in patient samples and examine its role in melanoma growth and metastasis.