Molecular Characterization Of E-cadherin-activated Rac Signaling
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Interactions between cells and their neighbouring cells control many important processes in the body. The adhesion molecule, E-cadherin, is a major protein that controls interactions between cells in epithelial tissues (e.g. breast, lung, gut). E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to the progression of many human cancers (especially common cancers such as breast and lung). Understanding how E-cadherin controls normal epithelial c ....Interactions between cells and their neighbouring cells control many important processes in the body. The adhesion molecule, E-cadherin, is a major protein that controls interactions between cells in epithelial tissues (e.g. breast, lung, gut). E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to the progression of many human cancers (especially common cancers such as breast and lung). Understanding how E-cadherin controls normal epithelial cell function will therefore provide key insights into the bases for tumor progression. In this study we will examine how E-cadherin signals to the interior of cells. We have recently discovered a new signaling pathway that is turned on when E-cadherin is activated. Understanding the fundamental elements of this signaling pathway will provide invaluable insights into how cells recognize one another during health and disease.Read moreRead less
Within the nervous system, neurons communicate through the release of neurotransmitter chemicals across connections between individual neurons (synapses). Before their release, neurotransmitters are stored inside nerve endings, within small membranous spheres called synaptic vesicles. Neuronal cell shape and the neuron's ability to migrate to different regions of the brain during development affect the way that the adult brain functions. Alterations in any of these brain functions may lead to di ....Within the nervous system, neurons communicate through the release of neurotransmitter chemicals across connections between individual neurons (synapses). Before their release, neurotransmitters are stored inside nerve endings, within small membranous spheres called synaptic vesicles. Neuronal cell shape and the neuron's ability to migrate to different regions of the brain during development affect the way that the adult brain functions. Alterations in any of these brain functions may lead to diseases affecting normal mental function. Ral is a small GTPase enzyme found in brain, and particularly in neurons. Small GTPases are responsible for regulating cell functions by acting as switches, turning biochemical processes on and off inside the cell. Within neurons, Ral is found on the surface of synaptic vesicles, implicating it in the regulation of neurotransmitter release. Other Ral functions have been demonstrated in non-neuronal cells that may be of particular significance in neuronal cells. However, no studies have previously investigated Ral function in the nervous system. The research proposed aims to establish what role RalA performs within neuronal cells, and by what biochemical mechanism it performs this role. Techniques of molecular biology, biochemistry and microscopy will be used to establish these functions. This research will lead to increased knowledge of the significance of this protein to cellular, and particularly neuronal cell function. This forms the basis for the understanding normal neuronal function, and for the identification of factors causing diseases of the nervous system. In time, such research aids in the development of specific therapies for sufferers of such diseases of the nervous system.Read moreRead less
Molecular Genetic Analysis Of BRCT Domain Function And RhoGEF Signalling In DNA-damage Response And Apoptosis.
Funder
National Health and Medical Research Council
Funding Amount
$195,691.00
Summary
Cancers arise as a consequence of a series of genetic changes, usually by mutation of DNA. DNA is consistently exposed to an array of damaging agents, but the majority of mutations are corrected by cellular repair mechanisms. We now know that if these mechanisms work normally, too few mutations persist for cancer to result. However if these DNA damage repair mechanisms are themselves faulty, a high mutation rate occurs and a high risk of cancer results. DNA damage has another outcome. If the dam ....Cancers arise as a consequence of a series of genetic changes, usually by mutation of DNA. DNA is consistently exposed to an array of damaging agents, but the majority of mutations are corrected by cellular repair mechanisms. We now know that if these mechanisms work normally, too few mutations persist for cancer to result. However if these DNA damage repair mechanisms are themselves faulty, a high mutation rate occurs and a high risk of cancer results. DNA damage has another outcome. If the damage is too extensive, the cell commits suicide, not because it cannot function, but because it senses the DNA damage and chooses to die. One poorly understood aspect of the response to DNA damage is how the cell senses the damage and activates the suicide process. We have discovered a novel gene that appears to play a role in this sensing and suicide signalling process. The mouse version of this gene can itself act as a cancer-causing gene. We propose, however, to study the equivalent gene in Drosophila melanogaster, a more powerful experimental system, to characterise in detail its role in these processes. In this way we hope to generate a much more detailed understanding of the way that cells deal with DNA damage and choose suicide when the damage is too severe.Read moreRead less
The Role Of Ezrin-radixin-moesin Proteins, Novel Binding Proteins For Advanced Glycation Endproducts, In Kidney Cells
Funder
National Health and Medical Research Council
Funding Amount
$493,220.00
Summary
High glucose levels in diabetes react with proteins to form AGEs and it is thought that this reaction may lead to kidney damage, which is one of the complications of diabetes. However, how this damage occurs is not completely understood. Cells need to maintain their shape and position for an organ to stay healthy. We have shown that AGEs affect kidney cells by interacting with and disturbing the function of proteins that maintain cell shape. We now want to study how this occurs.
Analysis Of Rho GTPase Signalling Pathways In An Epithelial To Mesenchymal Transition During Development Of The Mesoderm
Funder
National Health and Medical Research Council
Funding Amount
$409,500.00
Summary
A critical step in the progression of cancers that are derived from epithelial tissues is a transition from an epithelial cell type to a migratory mesenchymal cell type that can spread to other parts of the body. This change in cell behaviour also occurs, apparently by a similar mechanism, during the development of some normal tissue types. Here we propose to use an animal model of this process, coupled with advanced molecular genetic and cell biological techniques, to investigate a newly discov ....A critical step in the progression of cancers that are derived from epithelial tissues is a transition from an epithelial cell type to a migratory mesenchymal cell type that can spread to other parts of the body. This change in cell behaviour also occurs, apparently by a similar mechanism, during the development of some normal tissue types. Here we propose to use an animal model of this process, coupled with advanced molecular genetic and cell biological techniques, to investigate a newly discovered cell signalling mechanism required for the transition of cells from an epithelial form to a mesenchymal form. Understanding the molecular steps in this new pathway and discovering new genes involved will provide tools for understanding and preventing the metastasis of cancer cells.Read moreRead less
Regulation Of Signal Transduction By Cbl: Investigation Of Effects On The Cytoskeleton, Cell Adhesion And Cell Motility
Funder
National Health and Medical Research Council
Funding Amount
$256,527.00
Summary
Changes in cell adhesion and motility have been implicated in a wide range of human pathologies (e.g. immune, reproductive, mental, and cancerous disorders) . Cell adhesion and motility are tightly regulated by a group of proteins known as Rho-GTPases. Novel pharmacological agents that target signalling by Rho-GTPases have been demonstrated to profoundly affect tumour metastasis, as well as central nervous system regeneration following injury. Further exploitation of Rho-GTPase signal modulation ....Changes in cell adhesion and motility have been implicated in a wide range of human pathologies (e.g. immune, reproductive, mental, and cancerous disorders) . Cell adhesion and motility are tightly regulated by a group of proteins known as Rho-GTPases. Novel pharmacological agents that target signalling by Rho-GTPases have been demonstrated to profoundly affect tumour metastasis, as well as central nervous system regeneration following injury. Further exploitation of Rho-GTPase signal modulation, by detailed studies of the molecular mechanisms involved, could lead to significant advances in medical sciences. In particular, treatment of cancer and spinal injuries are likely to benefit from further development of Rho-signalling research.Read moreRead less
Elucidation Of Signalling Enzymes Regulating The Small GTPase RhoA
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Many normal and pathological processes in the human body depend on the ability of cells to attach to a biological surface (adhesion), spread out, or move to another site (migration). Examples of biological processes that require such events include the division and arrangement of cells in a developing embryo, or the ability of cancer cells to spread (metastasise). A driving force behind the attachment or movement of cells is their ability to rearrange a scaffolding called the cytoskeleton. The c ....Many normal and pathological processes in the human body depend on the ability of cells to attach to a biological surface (adhesion), spread out, or move to another site (migration). Examples of biological processes that require such events include the division and arrangement of cells in a developing embryo, or the ability of cancer cells to spread (metastasise). A driving force behind the attachment or movement of cells is their ability to rearrange a scaffolding called the cytoskeleton. The cytoskeleton is similar to the skeleton of the human body, in that it acts to maintain cell shape and rigidity. However, it is also actively reorganised to participate in many cellular processes, including cell attachment and movement. By furthering our understanding of how the cytoskeleton is rearranged, this will provide important insights not only into the basics of cell behaviour, but will also have important implications for a number of human disease states. This proposal aims to investigate mechanisms that regulate the reorganisation of the cytoskeleton. It is well established that the rearrangement of this scaffolding, in many different types of cells, is controlled by a family of proteins called the Rho family of small GTPases. One of the members of this family, RhoA, has a specific role in controlling cell attachment, and interestingly, has been implicated in the invasive and metastatic properties of human tumour cells. We have recently identified a protein that is responsible for controlling the activation of RhoA. This proposal aims to further our understanding of how this protein regulates RhoA, and therefore cell attachment and movement. Given that cell attachment and movement are important events contributing to the spread of tumours, this study may provide important insight into alternative approaches of controlling cell movement, and ultimately malignant progression.Read moreRead less