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
The Proteins Associated With The Neurotrophin Retrograde Transport Signalling Endosome
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
According to estimates taken from the Australian Bureau of Statistics population projection series, during the next forty years the incidence of Alzheimer's disease or a related dementia in Australia is predicted to increase by 254%. One of the key issues in neurobiology is to understand the mechanisms regulating the survival of nerve cells. Nerve Growth Factor (NGF) acts to cause nerve cell survival by being transported from the target tissue to the cell body in a discrete organelle described a ....According to estimates taken from the Australian Bureau of Statistics population projection series, during the next forty years the incidence of Alzheimer's disease or a related dementia in Australia is predicted to increase by 254%. One of the key issues in neurobiology is to understand the mechanisms regulating the survival of nerve cells. Nerve Growth Factor (NGF) acts to cause nerve cell survival by being transported from the target tissue to the cell body in a discrete organelle described as the Signalling Endosome. This process is termed Retrograde Axonal Transport. The signalling endosome is assembled in the nerve terminal and also contains proteins normally activated by NGF known as Second Messengers. Neurodegenerative diseases, such as Alzheimer's disease, occur due to the death of nerve cells and a disturbance of the retrograde axonal transport of NGF may contribute to this death. NGF has been shown to have clinical potential as it can promote neuronal repair and survival after injury. However clinical trials have demonstrated an unacceptable toxicity for this protein. Therefore, another approach taken to produce the restorative benefits of NGF is to stimulate second messenger pathways downstream from the NGF receptor. This approach could provide important new therapeutic potentials as we can target more selective components of these survival pathways and have a greater chance to find less toxic drugs. This project will identify the second messengers normally accompanying NGF from the nerve terminal which promote nerve cell survival. We will describe the way these proteins are recruited to the signalling endosome. Survival of nerve cells requires the activation of these proteins and we shall determine where this occurs. Understanding the molecular basis for the delivery of the retrograde survival signal in neurons is vital if new therapeutic strategies for the treatment of neurodegenerative disease and traumatic nerve damage are to be developed.Read moreRead less
Peripheral Nerve Grafts, Neurotrophic Factors, And Ex Vivo Gene Therapy In Visual System Repair
Funder
National Health and Medical Research Council
Funding Amount
$240,990.00
Summary
Worldwide, hundreds of thousands of people are victims of severe brain and spinal cord injuries, often as a result of motor vehicle accidents or sporting mishaps. Thousands more are added to this population each year. Because there is only limited intrinsic potential for the regeneration of axons in the adult mammalian central nervous system (CNS), traumatic injury almost always results in long-lasting functional impairments (mental and-or physical). The personal, social and economic costs for t ....Worldwide, hundreds of thousands of people are victims of severe brain and spinal cord injuries, often as a result of motor vehicle accidents or sporting mishaps. Thousands more are added to this population each year. Because there is only limited intrinsic potential for the regeneration of axons in the adult mammalian central nervous system (CNS), traumatic injury almost always results in long-lasting functional impairments (mental and-or physical). The personal, social and economic costs for the long-term clinical care and maintenance of functionally impaired patients are enormous. The proposed study aims to develop new and unique surgical and molecular approaches to CNS repair, using the rodent visual system as the experimental model. Pieces of peripheral nerve (PN) will be cellularly and genetically manipulated to produce increased levels of growth promoting factors. The modified PN tissue will then be transplanted into the injured CNS. It is expected that the increased levels of neurotrophic factors will promote and guide the regeneration of increased numbers of nerve fibres through the bridges and back into appropriate parts of the brain. A major goal is to determine if it is possible to harvest adult peripheral glia (Schwann cells) from the PN of a host, expand and engineer these cells ex vivo, and then graft these cells back into the same host to promote the repair of injured fibre tracts. Such an approach would be of considerable benefit in the surgical repair of CNS injuries in humans. It is thus intended that our experimental studies will lead to the development of new therapeutic strategies for the treatment of human brain and spinal cord injuries, resulting in improved functional outcomes and better quality of life after neurotrauma.Read moreRead less
Membrane Fusion In Axonal Regeneration: Molecules And Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$461,597.00
Summary
Limited nerve regeneration is the main obstacle for recovery from spinal cord and brain injuries. Understanding the cellular and molecular mechanisms underlying axonal regeneration is an essential step toward the development of novel effective therapies to enhance this process. In this proposal, we use the powerful molecular and genetic tools available for the small nematode worm C. elegans to identify and study axonal regeneration and discover the key molecules involved.
The Use Of Soluble Antagonists Of EphA4 In Spinal Cord Injuries
Funder
National Health and Medical Research Council
Funding Amount
$622,361.00
Summary
Permanent and limited recovery of function following spinal cord injury is a direct result of the lack of nerve regrowth through the injury. Our preliminary data suggest that antagonising the effects of EphA4, a protein involved in brain development, leads to substantial functional recovery simultaneous with nerve regrowth. In addition to designing new, more effective blockers of EphA4, we will study the signalling pathways that EphA4 activates to inhibit nerve regrowth.
Preventing Preterm Lung Disease - A Cell Therapy Approach.
Funder
National Health and Medical Research Council
Funding Amount
$460,610.00
Summary
Due to improvements in medical care, the survival of very premature babies has greatly improved over the past 20 years. However, many of these children are surviving with disability due to severe chronic lung disease of prematurity. Currently, there are no effective treatments for this lung disease. This project explores the use of placental stem cells as a lung repair and regeneration therapy - a therapy that can be given to the baby in the days immediately following its birth.
Novel Approach And Insights Into Muscle Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$642,401.00
Summary
The successful use of stem cell therapy absolutely requires the longterm intergration of the therapeutic cells into the target tissue. This application will adapt a chemotherapy-based strategy to drive the successful incorporation and growth of healthy muscle stem cells into diseased muscle. This study will both enhance our understanding of muscle stem cells and provide proof-of-principle for a universal approach to the uptake of stem cells by a target tissue.