Adult and embryonic stem cells have enormous therapeutic potential. Haemopoietic stem cells have been the most intensely studied and widely used in a therapeutic setting, yet we have only a patchy knowledge of the genes required for their proliferation and survival. I will use classical genetic screens in the mouse to identify genes that regulate stem cell behaviour. I will analyse two existing mutant mouse strains with reduced numbers of haemopoietic stem cells, and execute a novel genetic scre ....Adult and embryonic stem cells have enormous therapeutic potential. Haemopoietic stem cells have been the most intensely studied and widely used in a therapeutic setting, yet we have only a patchy knowledge of the genes required for their proliferation and survival. I will use classical genetic screens in the mouse to identify genes that regulate stem cell behaviour. I will analyse two existing mutant mouse strains with reduced numbers of haemopoietic stem cells, and execute a novel genetic screen utilising mice with a defect in the self-renewal of adult haemopoietic and neural stem cells, to find mice with a recovered stem cell compartment.Read moreRead less
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
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.
Molecular Mechanisms That Generate And Activate Muscle Stem Cells During Growth And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$596,086.00
Summary
This study aims answer long standing questions in the field of muscle stem cells. Understanding how stem cell-driven muscle repair occurs has profound implications for our understanding of the pathology and treatment of muscle disease. Muscular dystrophies and myopathies are amongst the largest group of inherited disorders to afflict the human condition. It is our hope that the results of this research will lead to a better understanding of how treatments, stem cell based or otherwise, could be ....This study aims answer long standing questions in the field of muscle stem cells. Understanding how stem cell-driven muscle repair occurs has profound implications for our understanding of the pathology and treatment of muscle disease. Muscular dystrophies and myopathies are amongst the largest group of inherited disorders to afflict the human condition. It is our hope that the results of this research will lead to a better understanding of how treatments, stem cell based or otherwise, could be employed to correct such disorders.Read moreRead less
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.
Long non-coding RNAs (lncRNAs) were considered to be junk, until recently. They cannot make protein so they were thought to be impotent. Despite this dogma, we studied the function of one lncRNA, in detail. Our data suggests it is a master regulator of mesoderm formation, the precursor of all internal organs. In this grant we will determine how this regulator works in normal development and how we might use this knowledge to design new therapies.
Control Of Germline Progenitor Cell Fate And Fertility By The MTORC1 Signaling Pathway
Funder
National Health and Medical Research Council
Funding Amount
$563,798.00
Summary
Maintenance and repair of many adult tissues is dependent on a rare population of stem cells. Germline stem cells are essential for male fertility although the mechanisms controlling these cells are poorly understood. We have identified a key role for the growth-promoting mTORC1 pathway in regulation of germline stem cell function. Our studies of upstream regulators and downstream targets of this pathway in germline cells promise unique insight into infertility, tissue regeneration and cancer.
Role Of Plzf – Sall4 Interactions In Germline Progenitor Function And Development
Funder
National Health and Medical Research Council
Funding Amount
$565,079.00
Summary
PLZF and SALL4 are critical stem cell factors and mutations in these genes are associated with developmental defects and cancer. SALL4 mutations are responsible for the malformation disease Duane-radial ray syndrome, while PLZF mutations lead to severe defects in the skeleton and gonads. We surprisingly found that PLZF and SALL4 interact and oppose each other’s functions. Our study of PLZF–SALL4 crosstalk will provide important insight into infertility, developmental disorders and cancer.
Molecular Mechanisms Underlying Induction Of Haematopoietic Stem Cells In The Embryo
Funder
National Health and Medical Research Council
Funding Amount
$577,573.00
Summary
Hematopoiesis, the processes of making blood cells, represents one of the best-defined paradigms for studying stem cell biology, but our understanding of how theses cells form in the embryo is incomplete.Our preliminary studies have revealed the existence of a novel "buddy cell" that directly regulates the induction of blood stem cells. This grant seeks to further these observations, and its general aim is to identify the molecular signals that the buddy cell uses to make blood stem cells
I am a developmental biologist studying how transcription factors regulate developmental processes. I have a particular interest in the MYST family of co-activators, their role in regulating self-renewal and lineage determination in stem cells, their role in oncogenesis and targeting these proteins to develop new cancer therapeutics.