The co-ordinated regulation of cellular functions by hormones is vital to be able to respond to both immediate and long-term environmental changes and stresses. The stress hormone, adrenaline, affects in particular, the cardiovascular system, causing constriction of small arteries and increases in the force and rate of contraction of the heart, by binding to, and activating, adrenergic receptor proteins present on the cell surface. Activation of these receptors is implicated in the development o ....The co-ordinated regulation of cellular functions by hormones is vital to be able to respond to both immediate and long-term environmental changes and stresses. The stress hormone, adrenaline, affects in particular, the cardiovascular system, causing constriction of small arteries and increases in the force and rate of contraction of the heart, by binding to, and activating, adrenergic receptor proteins present on the cell surface. Activation of these receptors is implicated in the development of cardiac hypertrophy, as well as ventricular arrhthymias following ischaemia and reperfusion. Understanding the precise mechanisms or pathways of activation of these receptors is, therefore, of direct relevance to the treatment of these important clinical disorders. We have recently discovered a new protein, Gh, involved in the regulation of cellular functions by adrenergic receptors. The aims of this proposal are to determine the importance of Gh in the heart and understand the molecular mechanisms that control the function of this protein. Such insights are of paramount importance as they have direct applicability to our understanding of the heart s response to stress and may lead to new diagnostic or therapeutic approaches for the treatment of cardiac diseases.Read moreRead less
Intracellular Calcium Signalling And Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$295,357.00
Summary
The liver is responsible for regulating the metabolism of carbohydrates and fats, the synthesis of proteins which transport fats around the body, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are controlled by hormones such as adrenaline and insulin. The actions of these and other hormones on the liver involves changes in the concentration of calcium in liver cells. In a number of diseases such as diabetes, fat mal ....The liver is responsible for regulating the metabolism of carbohydrates and fats, the synthesis of proteins which transport fats around the body, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are controlled by hormones such as adrenaline and insulin. The actions of these and other hormones on the liver involves changes in the concentration of calcium in liver cells. In a number of diseases such as diabetes, fat malabsorption, and liver failure, the balance and regulation of calcium in liver cells is abnormal. The aims of the present experiments are to investigate the mechanisms by which hormones regulate the flow of calcium into liver cells. The experiments will involve the measurement of calcium in different regions of liver cells using fluorescent dyes and high resolution microscopy, and the identification of structural proteins and organelles within the liver cell which are required to control calcium inflow. The results should show how an important type of calcium channel in liver cells works and is controlled. This knowledge will allow better treatment of diabetes, fat malabsorption and liver failure. The knowledge should also lead to improvements in liver transplant operations.Read moreRead less
A New Model Of Asthenospermia And A Candidate Gene For Multiple Ciliopathies
Funder
National Health and Medical Research Council
Funding Amount
$629,039.00
Summary
Though the analysis of a unique mouse strain (Mot1) we have identified a previously unknown cause of male infertility and lung disease. We hypothesis that the Mot1 line is a model of human primary cilia dyskinesia and that the Mot1 protein is involved in cilia function. Within this project we will define the consequences of a loss of Mot1 protein function, we will define its binding partners and we will screen for mutations in the corresponding human gene.
Role Of G-septin And Its Phosphorylation By PKG In Nerve Terminals
Funder
National Health and Medical Research Council
Funding Amount
$363,055.00
Summary
Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from nerve endings (exocytosis). These events are partly controlled by a signalling molecule, cGMP, which mainly stimulates the enzyme PKG. However, it has been largely unknown how PKG takes the signalling further. In previous studies supported by the NH ....Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from nerve endings (exocytosis). These events are partly controlled by a signalling molecule, cGMP, which mainly stimulates the enzyme PKG. However, it has been largely unknown how PKG takes the signalling further. In previous studies supported by the NHMRC we identified 3 proteins that are phosphorylated and activated by PKG: SF1 controls the expression of genes in all cells; N-STOP stabilises the microtubule cytoskeleton to facilitate neuronal differentiation; and G-septin, which is the focus of this proposal. We cloned G-septin as the 8th member of a family of genes that are essential for cell division. Some septins assemble as filaments that allow the two new daughter cells to finally separate. When the filament formation is perturbed certain septins end up in microscopic clumps that are found in the post-mortem brains of people affected by Alzheimer's disease, suggesting they might contribute to the disease. However, G-septin is a brain-specific septin, which we found in neurons and in nerve terminals, locations not normally associated with cell division. The only other known brain-specific septin, CDCrel-1, was recently found to regulate the protein machinery of exocytosis, but is an unlikely target for cGMP. We will examine the hypothesis that G-septin is also a regulator of exocytosis. We will determine whether G-septin represents a convergence point for cGMP signalling to control exocytosis. A better understanding of G-septin and exocytosis is crucial to understanding brain disorders and ultimately developing better therapies.Read moreRead less