Regulation Of Epithelial Migration By Scribble In Development And Wound Repair
Funder
National Health and Medical Research Council
Funding Amount
$516,078.00
Summary
The movement of epithelial cells within our body (the cells that form the thin protective layer on exposed bodily surfaces such as skin and the lining of internal cavities, ducts, and organs) is essential for our normal embryonic development as well as for healing of wounds following injury. Understanding how this movement is regulated is therefore a fundamental area of medical biology. Although much is known about the mechanics of how a cell moves, the signals used to coordinate this movement s ....The movement of epithelial cells within our body (the cells that form the thin protective layer on exposed bodily surfaces such as skin and the lining of internal cavities, ducts, and organs) is essential for our normal embryonic development as well as for healing of wounds following injury. Understanding how this movement is regulated is therefore a fundamental area of medical biology. Although much is known about the mechanics of how a cell moves, the signals used to coordinate this movement so as to ensure that each cell migrates to the right place during embryonic development or in response to a wound is not well understood. A number of lines of evidence suggest that proteins required for the correct orientation of cells within our body (a property of cells known as polarity) may be essential for this process. Mutation of the polarity protein Scribble in the fly, zebrafish and mouse causes a disorganization of epithelial tissues during embryonic development. We have now shown that Scribble is required for cells to orientate correctly so as to be able to move in response to a wound in tissue culture and also during embryonic development and wound healing in the mouse. It is currently unknown how Scribble regulates migration. Here we propose to identify the molecules that Scribble regulates to coordinate cell movement during development and tissue repair. These studies will provide new insights into the fundamental process of how cell movement is coordinated and could lead to novel strategies for improved treatment of tissue injuries.Read moreRead less
Cellular Mechanisms Controlling Neural Crest Cell Migration Along The Developing Gut
Funder
National Health and Medical Research Council
Funding Amount
$368,895.00
Summary
Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by ne ....Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by neuron precursors takes 5 days in mice and 6 weeks in humans. Studies of the mechanisms controlling the migration of neuron precursors along the gut have provided fundamental information about cell migration in general. Genetic studies in humans and mice have identified some of the genes that are necessary for the migration of neuron precursors along the gastrointestinal tract, but for some of the key genes, their precise role is unknown. We have recently developed a method for imaging living neuron precursors migrating through explants of embryonic mouse gut. In the current proposal we will meld imaging and genetic studies to understand how mutations in particular genes lead to migration defects. In particular, how do particular mutations affect the migratory behaviour of enteric neural precursors? We have also previously shown that neuron precursors migrate along the gut in close association with axons. We will examine the nature of these interactions - in particular, who is following whom, and what happens when cell migration and axon growth are uncoupled? These studies, which will investigate a number of critical aspects of the migration of neural precursors into and along the developing gut, are central to understanding how the enteric nervous system is established along the gastrointestinal tract.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
Migration And Differentiation Of Dendritic Cells And Monocytes In Inflammatory Arthritis.
Funder
National Health and Medical Research Council
Funding Amount
$280,000.00
Summary
Dendritic cells and monocytes are of critical importance to the development and persistence of inflammatory disease in rheumatoid arthritis. Blocking this process at key strategic intervention points is a major focus of research to improve disease treatment. These studies examine the critical processes and molecules that control the entry of these cells to the joint in mice, and the derivation of cells that contribute directly to bone damage in the disease.
The Role Of SKAM And Sphingosine Kinase In Wound Healing
Funder
National Health and Medical Research Council
Funding Amount
$281,340.00
Summary
Many aspects of wound healing are poorly understood. We have identified a novel cellular pathway that appears critically involved in controlling wound contraction. This project aims to characterise this cellular pathway to understand the exact mechanisms whereby it controls this critical aspect of wound healing. With this information we will develop topical therapeutics to aid the wound healing process.
Investigating Tumour Development And Metastasis Using A Novel Drosophila Cancer Model.
Funder
National Health and Medical Research Council
Funding Amount
$505,500.00
Summary
The majority of cancers are derived from epithelial cells. The primary cause of cancer related deaths is due to the ability of these epithelial cancer cells to migrate and invade other tissues within the body away from their primary tissue of origin (metastasise). This proposal seeks to understand the pathways that are important in regulating the processes of epithelial cell migration and invasion that are instrumental in promoting the metastatic spread of tumour cells. As controls usually opera ....The majority of cancers are derived from epithelial cells. The primary cause of cancer related deaths is due to the ability of these epithelial cancer cells to migrate and invade other tissues within the body away from their primary tissue of origin (metastasise). This proposal seeks to understand the pathways that are important in regulating the processes of epithelial cell migration and invasion that are instrumental in promoting the metastatic spread of tumour cells. As controls usually operate to induce cell death in any cell that attempts to break away and invade other tissues, this proposal also seeks to understand some of the pathways that are responsible for causing these cells to die. To carry out these investigations we have developed a novel Drosophila model of epithelial cancer development. We use this model because of the ease with which it is possible to carry out complex genetic analyses and so dissect the roles of the many different signalling pathways involved in these processes. The strength of the model is that it is dependent upon genetic alterations that are also implicated in the development and metastatic spread of many mammalian cancers, namely activating mutations in two genes, Ras and Notch. It is expected, therefore, to offer considerable insight into why these activated genes also cause the spread of cancer cells in humans.Read moreRead less
Dissecting The Molecular Mechanisms Driving Cell Migration During Neurulation Triggered By The Netrin Receptor, Neogenin
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
In humans, abnormalities in brain and spinal cord formation during early embryogenesis result in congenital syndromes such as spina bifida and anencephaly. These defects occur at a rate of 1-1000 pregnancies and are therefore a major contributor to pre- and perinatal deaths. In the early embryo, the brain and spinal cord begin as a hollow tube of cells (the neural tube) that subsequently expands into the complex structures seen at birth. It is known that the neural tube is formed by a complex pr ....In humans, abnormalities in brain and spinal cord formation during early embryogenesis result in congenital syndromes such as spina bifida and anencephaly. These defects occur at a rate of 1-1000 pregnancies and are therefore a major contributor to pre- and perinatal deaths. In the early embryo, the brain and spinal cord begin as a hollow tube of cells (the neural tube) that subsequently expands into the complex structures seen at birth. It is known that the neural tube is formed by a complex process in which early neural cells migrate toward the midline of the embryo and subsequently coalesce. This project seeks to determine the function of one molecular signaling pathway (the neogenin pathway) that has been implicated in driving these cell migration events. We will initially use the frog, Xenopus laevis, as our embryonic model since the developmental processes that form the Xenopus neural tube closely parallel those ocurring in the human embryo. This model will allow us to identify the molecules in the neogenin signaling pathway. We will also create mice that carry a mutation in the neogenin gene so that we can study neogenin function in the mammal. We anticipate that these studies will provide important insights into the development of the central nervous system and also into the aberrant molecular processes underlying neural tube defects in man.Read moreRead less