Molecular And Cellular Basis For Muscle Regeneration In Zebrafish.
Funder
National Health and Medical Research Council
Funding Amount
$541,104.00
Summary
Muscle repair occurs via the use of muscle stem cells, which provide skeletal muscle with its regenerative capacity. Muscle stem cells are particularly important in muscle diseases such as muscular dystrophies where muscle regeneration is an important factor in disease progression. We will identify the processes controlling muscle regeneration utilising zebrafish as a model organism. We hope this research will lead to an understanding of how muscle stem cells are generated.
The Role Of Scube Genes In Hedgehog Signal Transduction
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
Cancer often results form the miss-regulation and-or mutation of genes that control tissue formation in the developing embryo. Particular sets of genes combine to form a signal transduction pathway that coordinates the cell's response to its environment during the course of normal fetal growth. One such pathway is called the Hedgehog signal transduction pathway which has been shown to coordinated cell division and patterning within malignant and normal tissues. Genes encoding components of this ....Cancer often results form the miss-regulation and-or mutation of genes that control tissue formation in the developing embryo. Particular sets of genes combine to form a signal transduction pathway that coordinates the cell's response to its environment during the course of normal fetal growth. One such pathway is called the Hedgehog signal transduction pathway which has been shown to coordinated cell division and patterning within malignant and normal tissues. Genes encoding components of this pathway are mutated in the most common forms of human cancers. Understanding how this pathway is regulated is critical to designing strategies to treat the onset and progression of these cancers. The studies outlined in this grant plan to study a new component of this pathway that we have identified in our laboratory, in an easy to study vertebrate model, the zebrafish embryo. We plan to study how this class of proteins, termed scube proteins, acts to control activation of the pathway. We hope this will lead to a fuller understanding of this process, and at the same time help understand the nature of the end result of the patterning process within the muscle cells that we are studyingRead moreRead less
The Regulation And Function Of Cadherin-mediated Adhesion Within The Zebrafish Myotome.
Funder
National Health and Medical Research Council
Funding Amount
$436,773.00
Summary
Co-ordinating how cells interact with their neighbours and where different cells are positioned within an organ is the role of proteins termed cell adhesion molecules. They delineate and sort cells into different groups depending on which cell adhesion molecules are expressed on their surface. Cell adhesion molecules are also important during the onset of disease, in particular cancer, where the levels and type of cell adhesion molecules expressed on the surface of a cancer cell can determine ho ....Co-ordinating how cells interact with their neighbours and where different cells are positioned within an organ is the role of proteins termed cell adhesion molecules. They delineate and sort cells into different groups depending on which cell adhesion molecules are expressed on their surface. Cell adhesion molecules are also important during the onset of disease, in particular cancer, where the levels and type of cell adhesion molecules expressed on the surface of a cancer cell can determine how invasive or aggressive the cancer cell will become. However, despite the fundamental importance that cell adhesion plays in sorting out cells in every tissue, the exact basis of cell migratory behaviours that occur within the intact organism remain poorly defined. We have examined the ability of specific members of a particular class of cell adhesion molecules, the classical Cadherins, to control formation of muscle. To do this we have examined muscle formation within embryos of the zebrafish, a small embryologically accessible fresh water fish. We have determined how different cadherin molecules co-ordinate the final pattern of the myotome, the structure that gives rise to the majority of muscle in the early embryo. We have determined that differential cell adhesion drives cell sorting of specific muscle cell types via differential use of members of the classical cadherin family of proteins. This study aims to look further at the way that these proteins are regulated in different muscle cells of the forming body. By understanding how these molecules regulate cell sorting and adhesion within the zebrafish myotome we hope to be able to apply this knowledge to how these molecules control the formation of more complex tissues. Furthermore, we believe the implication of specific signalling pathways in the control of cadherin gene expression has particular implications for the role these proteins play in the progression of metastatic cancer.Read moreRead less
Specialised immune cells, called cytotoxic T cells, circulate through the body, and kill infected cells to protect us from disease. We discovered that a protein, DOCK8, is important for the regulation of T cell function. Importantly, humans with mutations in the DOCK8 gene suffer from a debilitating, and potentially lethal, immunodeficiency disease. This project will therefore elucidate the role of DOCK8 in immune cells, to better understand the consequences of DOCK8 deficiency for immunity.
Genetic Basis For Skeletal Muscle Formation And Regeneration In Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$876,005.00
Summary
How does muscle grow and repair after injury or disease? This basic question in the focus of the research in this fellowship. Specific cells are put aside during development to generate the growth and provide stem cells required for regeneration. Using the advantages of the zebrafish system I will record the action of different stem cell populations during growth and disease. I will define the genes required for stem cell action and utilize this knowledge to create new therapeutic pathways.
Three Dimensional Ex Vivo Modelling Of Neuromuscular Junction Formation
Funder
National Health and Medical Research Council
Funding Amount
$120,253.00
Summary
Re-establishing functional connections between neurons and muscle is an important step in the recovery process after neuromuscular injury or surgery. In order to study the connection forming process in isolation a biological model of nerve muscle connection formation is required. This study aims to buid a biological model consisting of neurons and muscles in a three dimensional environment and to assess the quality of the functional connections that develop.
Mechanisms Of Muscle Stem Cell Action In Injury And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$812,600.00
Summary
How do stem cells work in an organ or tissue to effect repair? Skeletal muscle is one of the few tissues that possesses the ability to regenerate after injury or disease but we understand very little about the processes that govern stem cell activation and the biology of self renewal, the mysterious process by which stem cell populations replicate themselves. Our zebrafish system will allow us to examine these questions directly in living muscle.
Characterisation Of The Regenerative Response In A Zebrafish Model Of Duchenne Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$435,750.00
Summary
Muscular Dystrophy is the most common lethal inherited disorder of children. Within dystrophic patients skeletal muscle fibres undergo cycles of muscle breakdown and regeneration until the regenerative response is exhausted, leading to a progressive muscle wasting. Regeneration of skeletal muscle is controlled by a specialised set of stem cells termed satellite cells that are activated to produce new muscle fibres in response to injury. As such satellite cells have been the targets of intense in ....Muscular Dystrophy is the most common lethal inherited disorder of children. Within dystrophic patients skeletal muscle fibres undergo cycles of muscle breakdown and regeneration until the regenerative response is exhausted, leading to a progressive muscle wasting. Regeneration of skeletal muscle is controlled by a specialised set of stem cells termed satellite cells that are activated to produce new muscle fibres in response to injury. As such satellite cells have been the targets of intense investigation for the development of cell based therapies for muscular dystrophies. We have developed a new vertebrate animal system in which to analyse muscular dystrophy and the control of satellite cell function, the zebrafish. We have shown that a mutation in a gene responsible for causing Duchenne Muscular Dystrophy in humans also causes a similar disease in Zebrafish. Zebrafish are an embryologically and genetically tractable model system in which to study muscle cell biology. The ability to visualise muscle growth within an optically transparent embryo and larvae, coupled with a large number of mutations affecting muscle patterning and growth suggest that it is a suitable model to explore muscle maintenance. The specific aims of this proposal are to determine in our new dystrophic zebrafish model, how regeneration controls the onset and pathology of muscle fibre loss. We wish to determine if muscle stems cells analogous to those known to function in mammalian muscle can be detected in zebrafish in normal and dystrophic muscle. We then plan to identify novel genes controlling muscle growth and regeneration through the genetic and embryological advantages that zebrafish as a model organism provide. We hope this will lead to a better understanding of how muscle stem cells are generated and are activated in muscular dystrophy and we hope this will open new avenues for muscle stem cell based therapies of the disease.Read moreRead less