Unravelling The Mechanism Coupling Synaptic Activity With Neurotrophin Signaling In The Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$640,815.00
Summary
Although active brain cells are known to survive for much longer than inactive ones, the mechanism underpinning this essential process has remained elusive. We have uncovered a direct coupling between neuronal activity and survival signals. The purpose of this grant application is to establish the molecular mechanism underpinning this coupling and understand how neuropathic pathogens manage to harness it with devastating effects to the brain.
Vesicular Trafficking Pathways Underpinning Neuronal Secretion And Survival
Funder
National Health and Medical Research Council
Funding Amount
$697,209.00
Summary
Plethora of diseases of the nervous system are caused by defects in vesicular trafficking including neurodegenerative diseases such as Alzheimer’s disease. I will explore the mechanisms underpinning synaptic vesicular trafficking using novel super resolution techniques and reveal the how secretory vesicles traffic to the plasma membrane, undergo exocytosis, and recycle. I will also explain how in the crowded environment of the presynaptic terminals, retrograde cargoes are transported back to the ....Plethora of diseases of the nervous system are caused by defects in vesicular trafficking including neurodegenerative diseases such as Alzheimer’s disease. I will explore the mechanisms underpinning synaptic vesicular trafficking using novel super resolution techniques and reveal the how secretory vesicles traffic to the plasma membrane, undergo exocytosis, and recycle. I will also explain how in the crowded environment of the presynaptic terminals, retrograde cargoes are transported back to the cell body thereby carrying survival signals.Read moreRead less
Determining Neuronal Connections Involved In Parkinson's Disease And Cocaine Addiction
Funder
National Health and Medical Research Council
Funding Amount
$343,300.00
Summary
Addictive behaviours in response to cocaine use and fine motor coordination that is affected in Parkinson's disease are both controlled by the same type of cells/neurons, i.e., dopamine neurons. However, the circuitry of these neurons varies from where they originate and the type of connections they make. By understanding the neuronal circuitry of these two circuitries in concert we will be able to gain important insight into their roles in adaptive and pathological brain function.
Prevention Of Neuron Death By Targeted Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$195,691.00
Summary
Neurotrophic factors are potent proteins that have the ability to keep nerves alive. They have therefore been used in clinical trials to treat motor neuron disease, but without success. A major reason for this appears to be the way in which the neurotrophic factors are delivered. Direct injections into the blood stream are a convenient way of getting these large proteins into the bloodstream, but this is not their normal mode of action. These proteins are normally provided by cells adjacent to t ....Neurotrophic factors are potent proteins that have the ability to keep nerves alive. They have therefore been used in clinical trials to treat motor neuron disease, but without success. A major reason for this appears to be the way in which the neurotrophic factors are delivered. Direct injections into the blood stream are a convenient way of getting these large proteins into the bloodstream, but this is not their normal mode of action. These proteins are normally provided by cells adjacent to the nerves. We have designed a system that more closely resembles this physiological mode of action which involves the delivery of neurotrophic factor genes, via the bloodstream, to the affected nerves. Once inside the nerves the factors are produced on site and, following their secretion, act locally and directly on the injured nerves.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
Delayed Neuronal Death After Peripheral Nerve And Spinal Cord Injury
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
After injury to the nervous system, even under optimal conditions for regeneration of broken nerve processes (axons), there is little chance of normal function being restored because few regrowing axons will find appropriate cells to connect with. The time taken for many regrowing axons to reach their targets can be so long that both the axons and their targets lose the ability to recognize each other. Equally importantly, some damaged nerve cells die over the months that follow an injury. This ....After injury to the nervous system, even under optimal conditions for regeneration of broken nerve processes (axons), there is little chance of normal function being restored because few regrowing axons will find appropriate cells to connect with. The time taken for many regrowing axons to reach their targets can be so long that both the axons and their targets lose the ability to recognize each other. Equally importantly, some damaged nerve cells die over the months that follow an injury. This slow loss of nerve cells can lead to progressive and ongoing deterioration. Given recent advances in our understanding of how to improve axon regeneration, the degree of functional recovery could be disappointing unless we know more about how to prevent these neurones from dying. This project will use rats as experimental animals to try to understand which types of nerve cells are likely to die or survive after injury to peripheral nerve trunks or to the spinal cord. We will investigate two regions of the nervous system that are commonly involved in injuries in people. After injuries to limb nerves, people lose sensation and movement and can unpredictably develop chronic conditions such as neuropathic pain (unrelated to the damage and often occurring spontaneously) as well as poor blood flow and wound healing in the hands-feet. After most injuries to the spinal cord, the lower part of the cord beyond the injury (in particular the lumbosacral cord controlling hindlimb movement and sensation and the function of bladder, bowel and sexual organs) is often disconnected from the brain leading to paralysis and disrupted control of pelvic organ function. We will identify and study specific populations of nerve cells with sensory (mainly pain-sensing) functions and four identified groups of nerve cells in the lumbosacral cord that project to the brain. Once we know which nerve cells do not survive, we will search for the likely causes of their death and ways to prevent it.Read moreRead less