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Regulation Of The Epithelial Sodium Channel By The Nedd4-like Protein KIAA0439
Funder
National Health and Medical Research Council
Funding Amount
$452,640.00
Summary
The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the distal nephron of the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that aris ....The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the distal nephron of the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that arise due to sodium imbalance. Furthermore, ENaC and the molecules involved in the channel regulatory cascade are potential candidate genes in defining the genetic causes of human hypertension and salt wasting disorders. Previous studies from our laboratories and by other groups have implicated Nedd4, a protein initially cloned by us, as a key player in regulating ENaC. Our recent data suggest that KIAA0439, a close relative of Nedd4, is also involved in ENaC control mechanisms. The work proposed in this application is an extension of our recent findings and will enable us to fully define how KIAA0439 regulates the activity of ENaC.Read moreRead less
Characterisation Of A Signal Transduction Pathway In The Early Embryo
Funder
National Health and Medical Research Council
Funding Amount
$208,500.00
Summary
The creation of embryos in the lab is important in assisted reproductive technology (ART) and potentially in cell therapies using embryonic stem cells. Yet, the development of the early embryo is not well understood. Creation of embryos in the lab is expensive and much of this cost is related to the relative inefficiency of the technology due to the high mortality of the resulting embryos. Typically, 45 - 80% of embryos produced by ART do not survive the first week. Hormones are essential chemic ....The creation of embryos in the lab is important in assisted reproductive technology (ART) and potentially in cell therapies using embryonic stem cells. Yet, the development of the early embryo is not well understood. Creation of embryos in the lab is expensive and much of this cost is related to the relative inefficiency of the technology due to the high mortality of the resulting embryos. Typically, 45 - 80% of embryos produced by ART do not survive the first week. Hormones are essential chemical messengers that regulate the normal functions of the body. Early embryo development is dependent on the action of special hormones that are produced by the embryonic cells themselves. The actions of these hormones are necessary for their normal survival. ART compromises the production and action of several of these hormones. Currently, there is not a detailed picture of how these embryonic hormones act on the embryo to promote their survival. Cells respond to outside hormones by changing the activity of a number intracellular proteins that act as on-off switches. The combinatorial pattern of 'switch' settings is modified by hormones, which in turn can act to change the pattern of gene expression. This project will extend our extensive studies on the nature of action of the well-described embryonic hormone known as PAF. The mechanism by which this hormone acts to signal changes in the pattern of the embryo's gene expression will be investigated. An understanding of how these embryonic hormones work will in the future allow for significant improvements in embryo viability.Read moreRead less
Effects Of Parvalbumin Up-regulation On Ca2+ Handling And Contractile Properties In Skeletal Muscle From Aged Mice
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
Ageing is accompanied by a loss of muscle function that may be due to an ageing-related impairment of calcium regulation. This project aims to improve calcium regulation in muscles of aged animals by enhancing the calcium buffering capacity via gene transfer. Whether this improves muscle function and muscle regeneration following injury in the aged will be assessed. Information from this project could lead to development of novel strategies to combat the loss of muscle function with ageing.
Role Of Non-classical Actions Of Androgens In Musculoskeletal Physiology
Funder
National Health and Medical Research Council
Funding Amount
$703,664.00
Summary
Androgens (male sex hormones) are important for growth-maintenance of muscle and bone. The classical action of androgens is to bind the androgen receptor (AR) and regulate target genes. They can also act via non-classical AR mechanisms through other cellular pathways. To understand the role of non-classical actions in the musculoskeletal system we will study mice in which androgens can only act via this pathway. This knowledge is important for the treatment of osteoporosis and muscle wasting.
Effects Of Atrial Natriuretic Peptide On The Sarcolemmal Na-K Pump In Rabbit Myocytes
Funder
National Health and Medical Research Council
Funding Amount
$225,500.00
Summary
The sodium pump transports sodium ions across cell membranes from the inside of cells to the outside. This maintains the concentration of sodium more than ten-fold lower on the inside than the outside. This transmembrane concentration gradient is essential for normal cell function. It is well established that the sodium pump is regulated by a variety of hormones. In a pilot study we have demonstrated that a hormone secreted by the heart, atrial natriuretic peptide, stimulates the sodium pump in ....The sodium pump transports sodium ions across cell membranes from the inside of cells to the outside. This maintains the concentration of sodium more than ten-fold lower on the inside than the outside. This transmembrane concentration gradient is essential for normal cell function. It is well established that the sodium pump is regulated by a variety of hormones. In a pilot study we have demonstrated that a hormone secreted by the heart, atrial natriuretic peptide, stimulates the sodium pump in single heart cells. This has not been reported previously. This study will examine the cellular mechanisms that mediate the stimulation of the sodium pump by atrial natriuretic peptide. A study on the effect of atrial natriuretic peptide on the regulation of sodium in heart cells is particularly important from the perspective of heart failure, a condition characterised by an inability of the heart to pump a sufficient amount of blood. While the underlying causes of heart failure vary widely activation of several hormone systems is a common feature regardless of the aetiology. It has already been well established in clinical practice that interfering with hormone activation by drugs improves symptoms as well as survival. Drugs have recently been developed that can increase levels of atrial natriuretic peptide. Since raised levels of sodium may contribute to important heart cell abnormalities in heart failure the effect of atrial natriuretic peptide on sodium export from the cells by the pump may have important implications for treatment of this serious and common condition.Read moreRead less
Store-operated Calcium Channels And Liver Function
Funder
National Health and Medical Research Council
Funding Amount
$241,477.00
Summary
The liver is responsible for regulating the metabolism of carbohydrates and lipids , the synthesis of proteins responsible for the transport of lipids in the blood, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are regulated by the changes in the free calcium concentration in the cytoplasmic space of liver cells. In a number of diseases such as diabetes, fat malabsorption, and liver failure, the balance and regulat ....The liver is responsible for regulating the metabolism of carbohydrates and lipids , the synthesis of proteins responsible for the transport of lipids in the blood, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are regulated by the changes in the free calcium concentration in the cytoplasmic space of liver cells. In a number of diseases such as diabetes, fat malabsorption, and liver failure, the balance and regulation of calcium concentrations in liver cells is abnormal. The cytoplasmic calcium signal can come either from the extracellular space, through channels in plasma membrane, or from the intracellular calcium-storing organelles. The aims of the present proposal are to investigate the properties of the calcium channels in the liver cell plasma membrane, and the mechanisms by which they are regulated. The experiments will involve the direct estimation of calcium inflow into liver cells, measured as an electric current through the plasma membrane by patch-clamp technique. The results should show how calcium channels in liver cells work and provide knowledge that can be used for better treatment of diabetes, fat malabsorption and liver failure.Read moreRead less
The Effect Of Dietary Fatty Acids On Cellular Calcium Handling Mechanisms In Cardiac Muscle
Funder
National Health and Medical Research Council
Funding Amount
$275,765.00
Summary
A major health problem in the developed countries is cardiovascular disease, which is manifest as high blood pressure, stroke, heart attack and abnormalities of heart rhythm, or cardiac arrhythmias. A western diet, ie. one high in animal fat, or saturated fats, may be to blame. Human epidemiological studies have shown that consumption of a diet high in saturated fats is correlated with a propensity to arrhythmias while a diet high in polyunsaturated fatty acids (PUFAs) can confer protection from ....A major health problem in the developed countries is cardiovascular disease, which is manifest as high blood pressure, stroke, heart attack and abnormalities of heart rhythm, or cardiac arrhythmias. A western diet, ie. one high in animal fat, or saturated fats, may be to blame. Human epidemiological studies have shown that consumption of a diet high in saturated fats is correlated with a propensity to arrhythmias while a diet high in polyunsaturated fatty acids (PUFAs) can confer protection from coronary heart disease and cardiac arrhythmias. The mechanisms underlying these effects are not fully understood. The contraction of the heart depends on changes in calcium inside the individual muscle cells. Abnormalities of the way calcium is handled in the cells leads to abnormalities of contraction and to a certain types of arrhythmia. Over the last 5 to 10 years, technological developments have enabled us to examine changes in calcium in living heart cells at microscopic level. It is possible to fill individual living cells with a fluorescent dye which changes either the magnitude or the wavelength of its fluorescence according to the ambient calcium concentration. Cells filled with these dyes are examined with a laser scanning confocal microscope, in which a very tightly focussed laser beam excites the dye and the resulting fluorescence is gathered by a computer controlled image analysis system. In this way we can measure the calcium concentration within the cells with a spatial resolution of about 1-1000 of a millimetre, and a time resolution of about 1-100 of a second. Using these techniques, we have found that supplementing the diet of rats with either PUFAs or saturated fats produces a dramatic change in the way that calcium is stored and released in their heart cells. This effect of dietary fats has not been reported before, and it may represent an important clue as to how these substances protect against many cardiac arrhythmias.Read moreRead less
ARC Centre of Excellence in Quantum Biotechnology. ARC Centre of Excellence in Quantum Biotechnology. The ARC Centre of Excellence in Quantum Biotechnology aims to develop paradigm-shifting quantum technologies to observe biological processes and transform our understanding of life. It seeks to create technologies that go far beyond what is possible today, from portable brain imagers to super-fast single protein sensors, and to use them to unravel key problems including how enzymes catalyse reac ....ARC Centre of Excellence in Quantum Biotechnology. ARC Centre of Excellence in Quantum Biotechnology. The ARC Centre of Excellence in Quantum Biotechnology aims to develop paradigm-shifting quantum technologies to observe biological processes and transform our understanding of life. It seeks to create technologies that go far beyond what is possible today, from portable brain imagers to super-fast single protein sensors, and to use them to unravel key problems including how enzymes catalyse reactions and how higher brain function emerges from networks of neurons. By building a diverse, multidisciplinary, and industry-engaged ecosystem, the Centre means to develop our future leaders at the interface of quantum science and biology and drive Australian innovation across manufacturing, energy, agriculture, health, and national security.Read moreRead less
Rhythmicity, Synchronicity And Spasm In Smooth Muscle
Funder
National Health and Medical Research Council
Funding Amount
$614,520.00
Summary
Many cellular systems undergo rhythmical spontaneous chemical and-or electrical activity . This activity, often referred to as pacemaking, is prevalent in many organs underlying brain waves or causing heart beats or rhythmic contractions of smooth muscle. Our studies on pacemaker rhythmicities in smooth muscle have revealed a novel mechanism, one which is entirely different to that responsible for heart pacemaking, the generally held model for electrical pacemakers. We aim to study the mechanism ....Many cellular systems undergo rhythmical spontaneous chemical and-or electrical activity . This activity, often referred to as pacemaking, is prevalent in many organs underlying brain waves or causing heart beats or rhythmic contractions of smooth muscle. Our studies on pacemaker rhythmicities in smooth muscle have revealed a novel mechanism, one which is entirely different to that responsible for heart pacemaking, the generally held model for electrical pacemakers. We aim to study the mechanism in depth so that we can fully describe its operation. This knowledge will provide insight into phenomena such as spontaneous contractions in blood vessels, lymphatic vessels and in the gastrointestinal tract, activities which are the norm and which are likely to have major influence on blood pressure, the propulsion of lymph and gut peristalsis. The knowledge will in the longer term lead to a better understanding of rhythmicities generally as far ranging as uterine contractions during childbirth to brain waves. An understanding of the pacemaker mechanism may also provide a key to understanding debilitating conditions such as vasospasm which can lead to death or serious disability.Read moreRead less