Disruption To Intracellular Trafficking As A Central Pathogenic Mechanism In Amyotrophic Lateral Sclerosis (ALS)
Funder
National Health and Medical Research Council
Funding Amount
$688,157.00
Summary
There are several different forms of ALS (MND), but the disease appears very similar in terms of symptoms and pathology. We have identified a common disease process shared by several different forms of ALS, which suggests that this is the underlying mechanism by which motor neurons die. This study will investigate whether we can develop new drug targets based on this mechanism in animal disease models. This may ultimately assist in the development of new treatments for ALS.
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
Effects Of Saccadic Eye Movements On Perception And Visual Memory.
Funder
National Health and Medical Research Council
Funding Amount
$255,750.00
Summary
We all make rapid eye movements, called saccades, three times a second all our waking lives. They allow us to direct our gaze at what catches our attention, but they sweep images across our retinas and alter all the linkages between the eyes and the brain. The question at the heart of this project is how the visual system maintains perceptual stability given the disruption to the flow of visual input that saccades necessarily cause. It has to do more than suppress disturbing signals; it has to l ....We all make rapid eye movements, called saccades, three times a second all our waking lives. They allow us to direct our gaze at what catches our attention, but they sweep images across our retinas and alter all the linkages between the eyes and the brain. The question at the heart of this project is how the visual system maintains perceptual stability given the disruption to the flow of visual input that saccades necessarily cause. It has to do more than suppress disturbing signals; it has to link the present with the past. In recent years we and others have made substantial progress toward answering this question. In this project we plan a four-pronged attack that will take us further. We anticipate that our results will reveal how the visual system maintains and adjusts its representations of space and time, integrates signals from before and after saccades, and regulates the flow of information from memory to achieve a seamless melding of the present with the past. This project is not directed at any particular clinical problem, but disturbances of perception and memory are aspects of many clinical conditions. If we succeed in our aims what we discover will constitute a major scientific discovery which should find application to many conditions in which perception and memory are disturbed, from dyslexia to brain damage and even affective disorders such as schizophrenia and depression.Read moreRead less
The Pathogenesis Of Motor Neuron Degeneration Caused By A Triplet Repeat Expansion In The Androgen Receptor Gene.
Funder
National Health and Medical Research Council
Funding Amount
$284,748.00
Summary
Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Ot ....Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Other symptoms include testicular wasting, reduced fertility and breast tissue enlargement. It is currently not known what causes motor nerves to degenerate in Kennedy?s disease. We are endeavouring to investigate the cause of Kennedy?s disease via the generation of a transgenic mouse carrying this mutation. It is only through a studying transgenic mouse affected by this disease can we begin to understand what is happening to nerves to cause them to die, and importantly, how can we prevent them from dying. These studies will also provide crucial information on the effects of sex hormones on nerves. As there is currently no treatment for Kennedy?s disease, an aim of this project is to investigate how we can treat this disease. This will be the first time that we can systemically test potential treatments and work toward preventing the degeneration of these nerves. Kennedy?s disease is related to a number of other neurodegenerative diseases including Huntington?s disease, which are caused by similar genetic mutations. All of these diseases are caused by degeneration of specific nerve cells. Evidence suggests that there may be similar mechanisms involved in all of these diseases. The results of this study will therefore help us to understand a range of diseases and may eventually lead to the development of therapeutic strategies to prevent their debilitating effects.Read moreRead less
Mechanisms Of Mechanotransduction In Primary Visceral Afferents
Funder
National Health and Medical Research Council
Funding Amount
$253,500.00
Summary
Mechanotransduction is the process whereby mechanical stimuli are converted into signals in sensory nerves. This forms the basis of touch, hearing, position sense and many aspects of internal perception. It also constitutes a major component of pain. Our group aims to discover the molecular basis of mechanotransduction in mammals, and in particular how it relates to signaling of events in the digestive system. We and our collaborators have been among the first to explore this question, and have ....Mechanotransduction is the process whereby mechanical stimuli are converted into signals in sensory nerves. This forms the basis of touch, hearing, position sense and many aspects of internal perception. It also constitutes a major component of pain. Our group aims to discover the molecular basis of mechanotransduction in mammals, and in particular how it relates to signaling of events in the digestive system. We and our collaborators have been among the first to explore this question, and have found that three genes are responsible for many aspects of mechanotransduction. Each gene is transcribed to produce a channel or pore in the membrane of sensory nerve fibres which responds to mechanical forces by allowing ions to enter and induce electrical signals. Our early findings in mice with disruption of individual genes indicate that a complex positive and negative interaction of these channels must underlie normal mechanotransduction. However, these channels must represent only a part of the transduction mechanism, with extracellular and intracellular anchors inevitably playing a major role. The identity of such anchoring proteins in mammals is currently emerging, and we are fortunate to have access to mice deficient in specific genes that will provide information about candidates for this role. Through our studies on mechanotransduction in the digestive system in parallel with our collaborators' studies on mechanotransduction in skin we shall not only identify the fundamental mechanisms of mammalian mechanotransduction, but also reveal which components of mechanotransducers are peculiar to the gut. Such peculiarities provide molecular targets for therapy of diseases in which alteration of mechanosensory signaling is itself an aim.Read moreRead less