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Wnt Signaling In Dopaminergic Neuronal Connectivity
Funder
National Health and Medical Research Council
Funding Amount
$564,721.00
Summary
A major obstacle in repairing the injured or diseased brain is inducing axons (nerve cell processes) to make the appropriate connections. This is especially true following cell replacement therapy (CRT) in Parkinson's disease (PD). We will examine the processes inducing axons in the dopamine pathways to grow. We hypothesize that Wnt signaling plays and important role and that therapeutic introduction of Wnt is required to repair the dopamine pathways following CRT in PD.
Regeneration And Repair In The Rodent Visual System: An In Vivo Gene Therapy And Neural Transplantation Study
Funder
National Health and Medical Research Council
Funding Amount
$426,000.00
Summary
In the adult human central nervous system (CNS), traumatic injury, stroke, or loss of nerve cells due to degenerative disease all result in long-term and severe functional impairments. The personal, social and economic costs associated with these neurological problems are massive. In the proposed work, gene therapy and transplant techniques will be used to develop new cooperative strategies for neural repair. The aims are to protect and-or replace damaged nerve cells (neurons) and promote the lo ....In the adult human central nervous system (CNS), traumatic injury, stroke, or loss of nerve cells due to degenerative disease all result in long-term and severe functional impairments. The personal, social and economic costs associated with these neurological problems are massive. In the proposed work, gene therapy and transplant techniques will be used to develop new cooperative strategies for neural repair. The aims are to protect and-or replace damaged nerve cells (neurons) and promote the long-distance regrowth of their processes (axons). The ultimate goal is to improve the treatment of human CNS injury and disease, leading to better functional recovery. We will use the visual system as our experimental CNS model. Viruses are novel tools that can be used for the introduction of foreign genes into cells. We will use modifed, non-harmful viral vectors to genetically alter retinal neurons. We will incorporate extra copies of known neuroprotective and-or growth-promting genes into retinal cells and analyze whether these genetically engineered neurons possess a greater ability to survive and regenerate their axons after injury. We will combine this approach with the transplantation of peripheral nerve bridges which are known to boost the regrowth of CNS axons. We will also test the effects of viral transfer of genes into retinal neurons in transgenic mice that have already been given an 'extra dose' of a neuroprotective gene. We will determine if different genes cooperate together to produce a synergistic therapeutic effect after CNS injury. The above studies focus on regeneration in what are essentially acute injury models. We are also interested in the restoration of circuitry in chronic situations, where the damage occured some time previously and neurons have already been lost. We will therefore graft neural precursor cells into the rat eye in an attempt to replace endogenous retinal neurons that are dying or have been lost due to injury.Read moreRead less
Identifying Genetic Pathways Underlying The Development Of Distinct Neuronal Subtypes Among Midbrain Dopamine Neurons.
Funder
National Health and Medical Research Council
Funding Amount
$462,709.00
Summary
There is an urgent need in the field of Parkinson's disease (PD) research to develop new strategies aimed at halting progression of the disease (neuroprotection) and alleviaing the symptoms (restorative therapy). This project employs a novel and innovative design to identify genes expressed specifically by the cell type most effected in PD and therefore provide new genetic targets for neuroprotective and resorative therapy.
Intraocular Transplantation And Regeneration Of Retinofugal Pathways In Rodents
Funder
National Health and Medical Research Council
Funding Amount
$370,937.00
Summary
In the adult human brain and spinal cord there is little or no intrinsic capacity for replacement of lost or dying neurons, and there is minimal spontaneous repair of nerve fibre pathways. Thus traumatic injuries, stroke, or loss of neurons due to chronic degenerative disease result in functional impairments that are usually severe and long-lasting. The personal, social and economic costs associated with these neurological problems are enormous. New ways must be found of protecting and-or replen ....In the adult human brain and spinal cord there is little or no intrinsic capacity for replacement of lost or dying neurons, and there is minimal spontaneous repair of nerve fibre pathways. Thus traumatic injuries, stroke, or loss of neurons due to chronic degenerative disease result in functional impairments that are usually severe and long-lasting. The personal, social and economic costs associated with these neurological problems are enormous. New ways must be found of protecting and-or replenishing nerve cells in damaged CNS gray matter, and new methods are also required to help reconstruct fibre tracts after injury. Using the visual system as an experimental model, the aims of the proposed work are to develop novel transplantation and surgical strategies to: (i) Incorporate new cells into retinae that have been selectively depleted of endogenous neurons (ii) Promote the effective regeneration of large numbers of adult retinal axons through prosthetic peripheral nerve bridging grafts and into host CNS distal to the injury. The results obtained from the first series of studies will not only be of direct relevance to the future treatment of human retinal degenerative disorders, but will also increase our overall understanding of how best to ensure the differentiation and stable integration of different types of transplanted cells within the compromised host CNS. The second series of experiments should lead to an entirely new approach to nerve pathway reconstruction, relevant to both brain and spinal cord injuries. The ultimate aim of this experimental work is to improve the management and treatment of human CNS injury and disease, leading to better functional recovery and rehabilitation.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