L-amino Acid Sensing By The Extracellular Calcium-sensing Receptor: Molecular, Cellular And In Vivo Studies
Funder
National Health and Medical Research Council
Funding Amount
$362,545.00
Summary
Recent work by Dr Conigrave and colleagues demonstrates for the first time that protein and calcium metabolism are linked at the molecular level by the widely distributed calcium-sensing receptor. The project will aim to demonstrate the physiological significance of this finding by testing whether L-amino acids, the building blocks of body protein, exert receptor-dependent control over the secretion and blood levels of hormones that regulate body calcium levels. It will further test the hypothes ....Recent work by Dr Conigrave and colleagues demonstrates for the first time that protein and calcium metabolism are linked at the molecular level by the widely distributed calcium-sensing receptor. The project will aim to demonstrate the physiological significance of this finding by testing whether L-amino acids, the building blocks of body protein, exert receptor-dependent control over the secretion and blood levels of hormones that regulate body calcium levels. It will further test the hypothesis by determining whether amino acids exert receptor-dependent control over the proliferation of bone forming cells and urinary excretion of calcium.Read moreRead less
Hormones are essential chemical messengers that regulate the normal functions of the body. Reproduction in particular is widely influenced by hormones. The development of the very early embryo and its implantation into the uterus is not well understood. A new class of hormone has been implicated in this process. This hormone, known as platelet-activating factor (or PAF) is special among hormones since it belongs to a class of chemicals known as phospholipids. This is quite uncommon. This hormone ....Hormones are essential chemical messengers that regulate the normal functions of the body. Reproduction in particular is widely influenced by hormones. The development of the very early embryo and its implantation into the uterus is not well understood. A new class of hormone has been implicated in this process. This hormone, known as platelet-activating factor (or PAF) is special among hormones since it belongs to a class of chemicals known as phospholipids. This is quite uncommon. This hormone can act in an apparently contradictory fashion. Its production by the embryo allows it to act back on the embryo to stimulate embryo growth and survival. The embryo (of some species) then releases other hormones which prevents the PAF from acting on the uterus. If this repression of the uterine response to PAF does not occur then PAF acts on the uterus to stop further progression of the pregnancy (luteolysis). Hormones act on cells via special cell proteins known as receptors. It seems that the receptor for PAF in the embryo and the uterus are different and may therefore result in triggering different cellular responses by these 2 tissues. We have available to us mice with mutations that stop the functioning of these two likely classes of receptors. The progress of pregnancy and the development of embryos in mice with these mutations will be studied as a means of defining how PAF acts in pregnancy. The embryo will be studied in detail to determine the nature of the changes induced within the embryo by PAF acting via its receptor. One of these receptors is an entirely new class of molecules not previously understood to be able to act as a cell signalling devise. This study will describe if and how this potential new receptor acts in the embryo, allowing future detailed investigation of its role in normal cell function. It will show how this single hormone can regulate both the uterus and embryo to have contradictory roles in the establishment of pregnancy.Read moreRead less
Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inf ....Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inflammation, and disorders of the immune system. The action of CSF-1 is mediated by the CSF-1 receptor (CSF-1R) which, when activated, controls gene regulation. In this proposal we will study CSF-1R activation and identify the genes regulated by CSF-1 with a view to characterize genes critical for macrophage development. These genes may provide potential targets for new pharmacological agents.Read moreRead less
Significance And Mechanisms Of Relative Progesterone Receptor Isoform Expression In Normal And Malignant Target Tissues
Funder
National Health and Medical Research Council
Funding Amount
$737,248.00
Summary
The ovarian hormone progesterone has a pivotal role in normal female physiology, in the uterus and ovary; in the mammary gland and in the brain. Human progesterone receptor, through which progesterone exerts its physiological effects, is expressed as two receptor proteins (PRB and PRA). These are identical except that PRA is shorter than PRB and present knowledge supports a role for both proteins in normal physiology. PR is also expressed in breast cancers, where one of its roles may be to inhib ....The ovarian hormone progesterone has a pivotal role in normal female physiology, in the uterus and ovary; in the mammary gland and in the brain. Human progesterone receptor, through which progesterone exerts its physiological effects, is expressed as two receptor proteins (PRB and PRA). These are identical except that PRA is shorter than PRB and present knowledge supports a role for both proteins in normal physiology. PR is also expressed in breast cancers, where one of its roles may be to inhibit oestrogen action and thereby limit tumour growth. A tumour which lacks PR would lack this capacity and this may be clinically associated with poorer prognosis. We have shown that primary tumours lacking PR are more likely to progress to secondary sites and this may provide support for this possibility. In addition, we have shown that over-expression of one PR isoform in breast cancers can be as biologically significant as lack of PR: tumours expressing predominantly one isoform were associated with poorer prognosis features.This project is aimed at investigating how PRA and PRB exert their effects on the range of progesterone targets in normal and malignant tissues. We will do this by determining whether PR isoforms are located in the same nuclear site in cells expressing one versus cells expressing both PR isoforms, to explore whether the proteins act separately in target cells. We will then ask whether the PR activity is different if only one isoform (PRA or PRB) is expressed versus both PRA and PRB. Another major issue which will be explored is the way in which the relative levels of PRA and PRB are controlled, and whether this is altered in breast cancers. Finally, we will explore the clinical significance of PR isoform expression. If achieved, the aims of this project will delineate the individual and combined action of - THIS FIELD WAS OVER 2000 CHARS, TEXT WAS REMOVED TO LODGE THE APPLICATION. A COPY OF THE ORIGINAL APPLICATION IS AVAILABLE FROM ARCHIVE-HARDCOPYRead moreRead less
Modulation Of Virus-cellular Receptor Interactions In Picornaviral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
Summary
Gastrointestinal viral infections of humans result in a wide variety of illnesses ranging from the common cold to infantile paralysis and viral myocarditis. Despite the wide range of tissues and organs targeted by these viruses, the manner in which infection is initiated is remarkably similar. The primary step in infection is the binding of a virus to a specific protein on the cell surface, similar to the lock and key analogy. This project seeks to investigate the nature of interactions between ....Gastrointestinal viral infections of humans result in a wide variety of illnesses ranging from the common cold to infantile paralysis and viral myocarditis. Despite the wide range of tissues and organs targeted by these viruses, the manner in which infection is initiated is remarkably similar. The primary step in infection is the binding of a virus to a specific protein on the cell surface, similar to the lock and key analogy. This project seeks to investigate the nature of interactions between representative picornaviruses and their cellular attachment proteins with a view to designing rational anti-viral strategies to block virus cell attachment and cell entry. Using the data raised when investigating why some viruses only infect certain cells, we plan to target human tumors cells based on their susceptibilty to different viruses.Read moreRead less
Regulation Of The Anti-tumour Immune Response By The Chemokine Decoy Receptor CCX-CKR
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Melanoma is a significant cause of cancer-related deaths in Australians. Death is usually due to metastasis of the cancer to the lungs and other organs. In this project, we will take advantage of unique mouse models to determine whether inhibition of the function of a novel protein can prevent melanoma growth and metastasis to different organs. The results of this study may lead to new therapeutic approaches to control malignant melanoma and other metastatic cancers.
The Role Of A Phosphorylated Ser/Tyr Bidentate Motif In Leukemia And Myeloproliferative Disorders
Funder
National Health and Medical Research Council
Funding Amount
$279,254.00
Summary
The ability of a normal cell to survive and grow is subject to tight control. Cancer cells escape both these controls and survive and grow in an deregulated manner. Many therapies that are in clinical use or in pre-clinical development target the growth of cancer cells. While such an approach has the advantage of being highly effective in stopping the advance of cancer cell growth, it may allow the long-term survival of some cancer cells and increase the possibility that these cells will become ....The ability of a normal cell to survive and grow is subject to tight control. Cancer cells escape both these controls and survive and grow in an deregulated manner. Many therapies that are in clinical use or in pre-clinical development target the growth of cancer cells. While such an approach has the advantage of being highly effective in stopping the advance of cancer cell growth, it may allow the long-term survival of some cancer cells and increase the possibility that these cells will become resistant to drug treatment leading to disease relapse. On the other hand, therapies that target the survival of malignant cells would be expected to pull the rug from underneath cancer by killing the malignant cells regardless of whether they are growing or not. We have identified a signalling device in normal blood cells that controls both the growth and survival of cells. This device is in effect a switch with 2 components both of which are normally turned on and off. These 2 components are differentially wired to to the cell transmitting unique signals. Importantly, we have found that this switch is faulty in blood cancers and is permanently on in some leukemias promoting their prolonged life-span. Targetting specific components of this unregulated switch may provide new and improved approaches for the development of therapeutics in the treatment of leukemia.Read moreRead less
Antigen Receptor Sharing By Lymphocytes During An Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$286,328.00
Summary
A successful immune response relies on the ability of immune cells to quickly mount a specific offensive against invading foreign pathogens like bacteria or viruses. The specificity of this offensive is governed by receptors that can recognise pathogens. To survive an infection the immune system must rapidly expand the number of immune cells that have receptors that recognise, and can therefore specifically combat, the infection. The underlying theory of immunology, the clonal selection theory, ....A successful immune response relies on the ability of immune cells to quickly mount a specific offensive against invading foreign pathogens like bacteria or viruses. The specificity of this offensive is governed by receptors that can recognise pathogens. To survive an infection the immune system must rapidly expand the number of immune cells that have receptors that recognise, and can therefore specifically combat, the infection. The underlying theory of immunology, the clonal selection theory, states that this expansion is mediated by the proliferation of immune cells selected on the basis of expressing a pathogen specific receptor. We hypothesise that in addition to this proliferation the immune system may also expand the number of immune cells expressing pathogen-specific receptors by transferring these receptors between cells by a means of cell-membrane sharing. Indeed, we have evidence that this does occur both in the test tube and in animals and can function to amplify the number of immune cells that can specifically recognise a pathogen and thereby help with immune response development. This grant aims to further advance our understanding of this novel phenomenon.Read moreRead less