The Role Of Gas6 And The TAM Receptors In Central Demyelination
Funder
National Health and Medical Research Council
Funding Amount
$506,416.00
Summary
In Multiple Sclerosis, oligodendrocytes, the myelin-producing cells of the brain, are damaged and myelin is lost in a process called demyelination. This process also involves the brain's immune cells, called microglia. Both cell types are influenced by a factor called Gas6, which signals through proteins called Tyro3, Axl and Mer. We have shown that levels of Gas6 can affect the severity of demyelination in mice. We plan to further study the effects of these proteins during demyelination.
Role Of SOCS 3 In Regulating Oligodendroglial Phenotype In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,187.00
Summary
The response of nerve cells, known as oligodendrocytes, to an inflammatory insult dictates the severity of demyelinating diseases such as multiple sclerosis (MS). We have previously discovered that a key protein in this response is the cytokine leukaemia inhibitory factor (LIF) which, by activating the LIF receptor expressed on these cells, limits their death and reduces the clinical impact on animal models of MS. However, the therapeutic benefit of LIF is incomplete and we do not completely und ....The response of nerve cells, known as oligodendrocytes, to an inflammatory insult dictates the severity of demyelinating diseases such as multiple sclerosis (MS). We have previously discovered that a key protein in this response is the cytokine leukaemia inhibitory factor (LIF) which, by activating the LIF receptor expressed on these cells, limits their death and reduces the clinical impact on animal models of MS. However, the therapeutic benefit of LIF is incomplete and we do not completely understand the mechanisms by which LIF exerts these effects. To maximise the treatment potential of LIF we need to understand how LIF receptor signaling is modulated in the nervous system. An important protein known to regulate the activity of LIF and of other cytokines in other organs of the body is the suppressor of cytokine signaling 3 (SOCS 3) molecule. We have recently shown that the expression of SOCS 3 is increased in an animal model of MS, indicating that it is likely to modulate the activity of LIF in this context. We plan to investigate the nature of this regulation. SOCS 3 might limit the efficacy of LIF but it could also limit the deleterious effect of unbridled LIF receptor signaling. To distinguish between these possibilities, we plan to study the impact of demyelinating disease in animals in which SOCS 3 is either deleted or overexpressed in oligodendrocytes. In this way, we should be able to learn how to optimise the therapeutic potential of LIF in MS and related nervous system diseases.Read moreRead less
The Role Of BDNF In Central Nervous System Myelination
Funder
National Health and Medical Research Council
Funding Amount
$478,235.00
Summary
Multiple Sclerosis (MS) is the most common neurological cause of disability in young adult Australians. The cause of MS is unknown and therapies are limited to reducing inflammation, which does not address the major problem of the disease: loss of myelin. This project directly investigates how myelin is formed and will identify key mechanisms in this process, which may eventually be developed into treatments for diseases such as MS.
The Role Of BMP4 Signalling In Oligodendrogenesis Following Central Demyelination
Funder
National Health and Medical Research Council
Funding Amount
$360,202.00
Summary
Multiple Sclerosis (MS) is the most common neurodegenerative disease affecting young adults. It is a disease that kills myelin cells, which are necessary support cells for neurons and are critical for their function. This research investigates the role that BMPs play in myelin cell production and repair. Our aim is to identify regenerative therapeutics for MS.
Cellular Responses To Oligodendrcyte Apoptosis: Modeling The Early Pathogenesis Of Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$460,037.00
Summary
In Multiple Sclerosis, oligodendrocytes (the myelin-producing cells of the brain) are damaged and myelin is lost. This process results in damage to nerve cells. We have generated a model of oligodendrocyte death that results in nerve cell damage. We will use this model to understand how nerve cells become damaged when oligodendrocytes die and whether the brain can make new oligodendrocytes to protect nerve cells from further damage.
Myelin Repair By Neural Stem Cells Genetically Modified To Secrete Growth Factors TGFbeta Or IGF-1
Funder
National Health and Medical Research Council
Funding Amount
$199,165.00
Summary
The goal is to locally modify the environment in demyelinating lesions to enhance repair and recovery of function. We will use undifferentiated neural stem (progenitor) cells (NSC) as gene delivery vehicles to supply therapeutic growth factors to areas of damage. Implanted NSC integrate readily into the brain, restoring lost functions, without causing damage. They respond to tissue damage by differentiating into appropriate cells to repair defects, features which are particularly valuable where ....The goal is to locally modify the environment in demyelinating lesions to enhance repair and recovery of function. We will use undifferentiated neural stem (progenitor) cells (NSC) as gene delivery vehicles to supply therapeutic growth factors to areas of damage. Implanted NSC integrate readily into the brain, restoring lost functions, without causing damage. They respond to tissue damage by differentiating into appropriate cells to repair defects, features which are particularly valuable where endogenous myelin repair mechanisms have failed. The first approach will determine whether NSC engineered to secrete Insulin Like Growth Factor-1 (IGF1) promote myelin repair. IGF-1 is a potent stimulator of oligodendrocytes, the myelinating cells in the brain. Itstimulates oligodendrocyte proliferation, differentiation and myelin formation so it may reverse the demyelination and oligodendrocyte loss which are hallmarks of disease. The second strategy is to use NSC to deliver TGF-beta directly to demyelinated areas. TGF-beta suppresses autoimmune responses and is central to recovery from episodes of demyelination in multiple sclerosis and mouse models of immune demyelination. Two mouse models of demyelination will be used to determine the effect of implanted genetically modified NSC; inherited Krabbe disease in which a biochemical defect produces progressive toxic damage to myelinating cells, and injection of an antibody to myelin oligodendrocyte glycoprotein, which induces immune-mediated myelin damage. The behaviour and survival of IGF-1 or TGF-beta secreting NSC, the impact on the quantity of myelin, number of oligodendrocytes and nature of the cellular response to therapy will be quantified. The need for effective therapy of demyelination is urgent. Successful delivery of growth factors to support myelin repair combined with oligodendrocyte replacement would be a significant advance towards treatment for MS, Krabbe disease and other severe neurological disorders.Read moreRead less