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Research Topic : Regulation of protein synthesis by calcium
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    A Single Fibre Approach To The Study Of Regulation Of Protein Synthesis In Skeletal Muscle

    Funder
    National Health and Medical Research Council
    Funding Amount
    $420,039.00
    Summary
    Skeletal muscle is the most abundant tissue in the human body and accounts for more than 40% of body weight. Loss of muscle mass is a major cause of frailty and loss of functionality in the elderly and is also a common feature of many chronic diseases such as cancer, HIV, arthritis and chronic heart failure. Changes in protein synthesis are intrinsically associated with alterations in muscle mass, which is integral to health, physical performance and independent living. In this project we aim to .... Skeletal muscle is the most abundant tissue in the human body and accounts for more than 40% of body weight. Loss of muscle mass is a major cause of frailty and loss of functionality in the elderly and is also a common feature of many chronic diseases such as cancer, HIV, arthritis and chronic heart failure. Changes in protein synthesis are intrinsically associated with alterations in muscle mass, which is integral to health, physical performance and independent living. In this project we aim to answer some important outstanding questions regarding the regulation of protein synthesis in mammalian skeletal muscle using a novel, single cell approach. Results obtained within the framework of the project will contribute to the understanding of the regulation of cellular and molecular events underpinning protein synthesis in muscle, which is critical for developing effective strategies of treatment and management of various medical conditions to prevent muscle wasting.
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    Lipid Metabolism In The Aromatase Knock-out Mouse (ArKO)

    Funder
    National Health and Medical Research Council
    Funding Amount
    $408,055.00
    Summary
    Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermi .... Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermineralisation of the bones, intra-abdominal obesity, hypercholesterolaemia and insulin resistance. We are addressing the mechanisms of all of those phenotypes but in the present application we focus on the abnormalities in lipid metabolism. Thus we will seek to understand the increase in adiposity by examining the role of oestrogen in lipid synthesis, oxidation and breakdown in adipose tissue from intra-abdominal sites. We will also examine the role that oestrogen plays in cholesterol uptake, synthesis and catabolism by the liver as well as fatty acid synthesis and oxidation by the liver. These studies will be correlated with whole body parameters such as feeding behaviour, physical activity, energy expenditure, glucose and fat oxidation rates. We will also examine the effect of feeding a high cholesterol or a high fat diet on lipid metabolism in the oestrogen deficient animals, and we will determine the effect of oestradiol and isoflavone replacement on the phenotype. In this way we aim to reach a better understanding of the multiplicity of roles that oestrogens play in the regulation of lipid and cholesterol metabolism in both males and females. The results of such studies will be the development of better strategies to deal with pathologies resulting from disturbances in cholesterol and lipid metabolism.
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    In Vivo And In Vitro Regulation Of Calcium Transport By Calcitriol

    Funder
    National Health and Medical Research Council
    Funding Amount
    $63,582.00
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    Funded Activity

    Assessment Of Calcium Signaling In Breast Cancer Cells Associated With Epithelial-mesenchymal Transition

    Funder
    National Health and Medical Research Council
    Funding Amount
    $116,762.00
    Summary
    This research will assess the role of specific proteins that control cell function in a process which is important in the spread of cancer cells throughout the body. The work is aimed at identifying new targets for drugs that may be used to prevent or stop the spread of breast cancer cells to other organs such as the brain and liver.
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    Regulation Of Nuclear Calcium Concentration In The Life Or Death Of Cells

    Funder
    National Health and Medical Research Council
    Funding Amount
    $195,047.00
    Summary
    The nucleus is the most prominent of all cell organelles and contains the primary genetic material for cellular development and growth. It performs some of the most important functions in the life and death of all living cells. However, little is known about many of the regulatory signals and events that control nuclear function. We will use new genetically-encoded sensor molecules that a living cell can be instructed to produce at various internal locations to explore important features of cell .... The nucleus is the most prominent of all cell organelles and contains the primary genetic material for cellular development and growth. It performs some of the most important functions in the life and death of all living cells. However, little is known about many of the regulatory signals and events that control nuclear function. We will use new genetically-encoded sensor molecules that a living cell can be instructed to produce at various internal locations to explore important features of cell control. This study will look specifically at how changes in the concentration of ionised Ca2+ in the nucleus control the switching on of genes and the initiation of programmed cell death pathways. This information is of significance to our understanding of normal cell growth and development, as well as abnormal growth (e.g. cancer).
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    STRUCTURAL AND FUNCTIONAL INTERACTIONS BETWEEN THE II-III LOOP OF THE SKELETAL DHPR AND THE RYANODINE RECEPTOR

    Funder
    National Health and Medical Research Council
    Funding Amount
    $410,250.00
    Summary
    The project has implications for neuromuscular diseases and for muscle weakness in general and in the elderly, all of which are significant health issues. The results will elucidate molecular mechanisms in muscle contraction and will provide a basis for drug design and treatment of muscle disorders. Respiration and locomotion depend on changes in calcium concentration inside muscle cells. Cardiovascular function, neuronal activity and immune responses also depend on the release of calcium from i .... The project has implications for neuromuscular diseases and for muscle weakness in general and in the elderly, all of which are significant health issues. The results will elucidate molecular mechanisms in muscle contraction and will provide a basis for drug design and treatment of muscle disorders. Respiration and locomotion depend on changes in calcium concentration inside muscle cells. Cardiovascular function, neuronal activity and immune responses also depend on the release of calcium from internal stores. Ryanodine receptor (RyR) calcium channels, either alone or in combination with a different internal calcium channel, regulate calcium release in each of these diverse functions. The essential nature of RyRs is underlined by death at or before birth when RyR expression is defective. Genetic defects in the RyR cause cardiac arrhythmias, malignant hyperthermia and central core disease. RyR function is compromised in heart failure and fatigue. The key role of RyRs makes them a potential therapeutic target, but they are not used as such because of the limited knowledge of the nature and structure of their regulatory sites. Electrical signals from the brain are able to release calcium from internal stores in muscle and initiate muscle contraction by virtue of a physical interaction between two calcium channel proteins, a surface membrane channel and the RyR. The molecular basis of this protein-protein interaction is is not understood and is a subject of this proposal. We will (a) solve the structure of one part of the surface channel that is known to contribute to the protein-protein interaction with the RyR, (b) determine the amino acid residues that interact with each other and (c) evaluate the functional consequences of the the binding of proteins. Understanding more about RyR regulation will pave the way for rational drug design and the eventual use of the RyR as a therapeutic target.
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    Funded Activity

    Charting The Interface Between Cellular Metabolic States And Gene Regulation

    Funder
    National Health and Medical Research Council
    Funding Amount
    $653,196.00
    Summary
    The research successes of Molecular Biology and Biochemistry have given us detailed pictures of the regulatory and metabolic states of cells and tissues, yet we know little about how these states affect each other. We hypothesise the existence of regulatory interactions between ribonucleic acids, enzymes and metabolites to connect gene expression and metabolism. We will employ novel RNA Biology methods to discover such regulatory interactions in medically important cellular contexts.
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    Funded Activity

    Calcium Signaling And Epithelial-mesenchymal Transition: A New Approach To Identifying Pharmacological Targets For Metastasis

    Funder
    National Health and Medical Research Council
    Funding Amount
    $561,645.00
    Summary
    The largest killer of women with breast cancer is disease that has spread e.g. to brain, bones, lungs. Once breast cancer has spread in this way to secondary sites, also known as metastatic disease, then there is limited treatment available and generally therapy is palliative only. Our work describes experiments that will help us understand the process of metastasis and provide new avenues for drug discovery in metastatic disease, thus helping women who have a poor prognosis.
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    Funded Activity

    Regulation Of Genes By Changes In Blood Calcium

    Funder
    National Health and Medical Research Council
    Funding Amount
    $174,295.00
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    Funded Activity

    The Role Of Calcium In The Control Of Red Blood Cells

    Funder
    National Health and Medical Research Council
    Funding Amount
    $394,516.00
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    Showing 1-10 of 12109 Funded Activites

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