The Role Of Innate Immune Responses In Cardiac Muscle Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$543,678.00
Summary
Heart attack is a life-threatening disease that damages heart muscle. Zebrafish can naturally restore lost heart muscle after injury, providing a model to understand mechanisms of heart regeneration. Here, we will explore previously uncharacterized events involved in heart regeneration, with particular focus on the immune response. We will study how immune responses are involved in heart muscle regeneration in zebrafish to find new insights for repairing damaged muscle in the human heart.
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
Identification And Characterization Of The Molecular Mechanisms Of Cardiac Muscle Regeneration Regulated By The Epicardium In Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$540,772.00
Summary
Heart attack is a life-threatening disease that damages cardiac muscle. The human heart cannot create new muscle after the damage, which partly contributes to the high morbidity and mortality of this disease. Unlike humans, zebrafish, a small tropical freshwater fish, can naturally create cardiac muscle after injury. In this project, we will understand at the molecular level how zebrafish regenerate cardiac muscle, and provide insights for repairing damaged muscle in the human heart.
GTPase Regulation Of The Hippo Organ Size-control Pathway
Funder
National Health and Medical Research Council
Funding Amount
$570,334.00
Summary
The Hippo pathway is a key regulator of tissue growth. It was first discovered in vinegar flies and plays a similar role in mammals. We aim to define the mechanism by which two proteins, Pix and Git, control tissue growth by regulating the Hippo pathway. These studies will be performed in flies. Our studies will shed light on how tissue growth is controlled, and have the potential to inform the way that we treat human cancers and tissue growth disorders.
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.
Systemic Approaches Of Muscle Stem Cell Quiescence And Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$532,883.00
Summary
In the repair of injured muscles, after physical exercise, as part of the ageing process, and in muscle disorders, activated muscle stem cells proliferate and differentiate to replace affected tissues. The aim of this project is to apply systemic, genome-wide approaches to identify the gene networks involved in the balance between the differentiation or the self-renewing state of muscle stem cells.
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.
The Role Of Immune Cells And The Transcription Factor Hmga1 In Boosting Neural Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$375,561.00
Summary
Brain trauma and neuro degenerative diseases are prevalent conditions that cause life-long impact and severe disability. Currently there are no therapeutical options available and the prognosis for recovery is very poor. We recently determined the crucial and beneficial role of inflammation in neural regeneration. The inflammatory signals that initiate regeneration are not known. This proposal seeks to identify signals and gene programs that regulate the inflammation induced regeneration respons ....Brain trauma and neuro degenerative diseases are prevalent conditions that cause life-long impact and severe disability. Currently there are no therapeutical options available and the prognosis for recovery is very poor. We recently determined the crucial and beneficial role of inflammation in neural regeneration. The inflammatory signals that initiate regeneration are not known. This proposal seeks to identify signals and gene programs that regulate the inflammation induced regeneration response.Read moreRead less
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.
In Australia, chronic kidney disease costs >$1 billion per annum and can only be treated by dialysis or transplantation. Your kidney function depends upon what happened during your development as all the functional units of the kidney are made prior to birth from a stem cell population that then disappears. We have found a way to recreate these stem cells from adult cells. In this project, we will optimise this process and investigate whether regenerated stem cells can repair an adult kidney.