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.
Muscle Fusion Defects May Be A Common Cause Of Human Dystrophies
Funder
National Health and Medical Research Council
Funding Amount
$391,419.00
Summary
While muscle fusion is a crucial step of muscle formation, it is surprising that human muscle diseases were never associated with muscle fusion defects. We have recently undertaken a genome-wide functional screen using a mouse muscle cell line. We identified 21 genes that were previously associated with muscle dystrophies in human. The aim of this project is to examine the role of those genes during muscle fusion in vivo, using the chick embryo, mouse mutants and lines from patients as models.
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
Many human muscle diseases are caused by mutations in genes encoding skeletal muscle actin. Actin is a major building block of the sarcomere, the engine of muscle contraction. Our studies have identified a mutation in chaperonin, the main protein-folding complex responsible for actin folding, which results in a muscle defect. These results have led to a novel hypothesesis, which we test in this grant, namely that as the chaperonin complex can act as a modulator of of muscle disease.
Determining The Pathobiology Of Human Sarcomeric Myopathies Using Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$509,541.00
Summary
Laing muscular dystrophy and ACTA1 congenital muscular dystrophy are severe muscle diseases with high morbidity. We will create zebrafish strains that carry these diseases and use these to understand the causes of muscle failure and investigate possible areas of treatment for these conditions.
Modelling Laminin Mediated Adhesion And Congenital Muscular Dystrophy In Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$586,076.00
Summary
Congenital Muscular Dystrophy (CMD) is a muscle wasting conditions arising from mutations in the Lamina alpha 2 gene (lama2) gene. We have established zebrafish as a model system in which to determine the mechanistic basis of CMD pathology. We have isolated mutations in the zebrafish Lama2 gene and have determined that Lama2-deficient zebrafish accurately model the human condition. We aim to use the advantages of the zebrafish system to model treatments for muscular dystrophy
We will apply genome-wide approaches to identify the gene networks that regulate the self-renewal and the differentiation of muscle stem cells and their fusion to muscle fibres. These studies will deliver the first characterisation of the molecules and pathways implicated in these processes, which are essential steps of muscle growth.
Evaluation And Design Of Therapeutic Strategies Utilizing Zebrafish Genetic Models Of Duchenne Muscular Dystrophy.
Funder
National Health and Medical Research Council
Funding Amount
$632,438.00
Summary
Duchenne and Becker Muscular Dystrophy (MD) are allelic muscle wasting conditions arising from mutations in the dystrophin (DMD) gene. We have established zebrafish as a model system in which to determine the mechanistic basis of DMD pathology. We have isolated mutations in the zebrafish dystrophin gene and have determined that Dystrophin-deficient zebrafish accurately model the human condition. We aim to use the advantages of the zebrafish system to model treatments for muscular dystrophy.
Genetic Basis For Skeletal Muscle Formation In Development And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$751,854.00
Summary
Inherited skeletal dystrophies and myopathies are devastating and debilitating disease for which there are no cures and general muscle wasting is major health problem for a significant number of older Australians. Understanding how muscles form, grow and are maintained in model system, the Zebrafish, will provide avenues for treatment of these diseases. We will create models of human muscle diseases in zebrafish and test the usefulness of different therapeutic approaches we develop.
Systemic Approaches Of Myoblast Fusion In Vertebrates
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Myoblast fusion is a poorly understood process of crucial importance during muscle growth and repair. Furthermore, engineered myoblasts can be introduced to fuse with mature muscles, forming a stable hybrid organ within the adults, thus offering novel therapeutic possibilities in the future. In this research, we will undertake the first systemic, genome-wide approach to identify and characterise the gene networks underlying muscle fusion in vertebrates.