After The Cloning Of The HMSNL Gene: Molecular Pathogenesis Of The Disease
Funder
National Health and Medical Research Council
Funding Amount
$258,564.00
Summary
We have completed an NHMRC-funded study, where we identified the gene for a severe disorder of the peripheral nervous system. The disease, hereditary motor and sensory neuropathy - Lom (HMSNL), presents with gait disturbances, difficulty in using the hands, muscle weakness and wasting and sensory loss. The concomitant impairment of the insulating myelin sheath surrounding nerve fibres (facilitating nerve conduction) and of the nerve fibres themselves suggests that the molecular defect lies in th ....We have completed an NHMRC-funded study, where we identified the gene for a severe disorder of the peripheral nervous system. The disease, hereditary motor and sensory neuropathy - Lom (HMSNL), presents with gait disturbances, difficulty in using the hands, muscle weakness and wasting and sensory loss. The concomitant impairment of the insulating myelin sheath surrounding nerve fibres (facilitating nerve conduction) and of the nerve fibres themselves suggests that the molecular defect lies in the basic mechanisms of interaction between the two main types of cell in the peripheral nervous system: the myelin-producing Schwann cell and the neuron. The two cells form the most complex system of communication in the human body, where signaling from one is vital for the development, functioning and survival of the other. Very little is known about the molecular mechanisms of this communication. At the same time, knowledge of the normal mechanisms of interaction is the key to better understanding of the mechanisms of disease in the peripheral nervous system and of the causes and possible prevention of the impairment of function. The newly identified HMSNL gene is probably involved in the signaling necessary for the development and functioning of the Schwann cell and for the survival of the nerve fibres. To gain an insight into the nature of the signaling cascade, we propose to use several complementary experimental approaches. We will create a mouse model of the human disease, to study its very early stages and subsequent evolution. In parallel, we will use molecular techniques and a yeast model, to identify other steps in the signaling cascade. The NHMRC-funded study will be part of a larger project conducted in collaboration with leading laboratories in the UK and the Netherlands, where other aspects of the molecular basis of the disease and of the role of the new gene will be examined.Read moreRead less
Identification And Function Of Kv7-M-channels In Axons Of Cortical Neurons
Funder
National Health and Medical Research Council
Funding Amount
$324,930.00
Summary
Membrane proteins permeable to potassium ions provide an important break during hyperexcitability of nerve cells in the brain. In this proposal I will study the function of a unique member of potassium channel protein (the M-channel) located at key regions of nerve cells; the axon. The results will provide important insights into the elementary steps of nerve cell excitability, and a better understanding of M-channel related diseases including neonatal epilepsies and chronic nerve pain.
Genetic Bases For Charcot-Marie-Tooth And Hereditary Sensory Type 1 Neuropathies
Funder
National Health and Medical Research Council
Funding Amount
$618,055.00
Summary
This project aims to identify the defective gene in a hereditary disease of peripheral nerve. The hereditary disorders of peripheral nerve form the commonest group of human genetic diseases, collectively called Charcot-Marie-Tooth neuropathy. Although few hereditary nerve diseases are fatal most cause lifelong disability. All cause weakness of the lower legs and later weakness and wasting of the muscles of the arm and hand. Affected individuals have difficulty running, frequent falls with gradua ....This project aims to identify the defective gene in a hereditary disease of peripheral nerve. The hereditary disorders of peripheral nerve form the commonest group of human genetic diseases, collectively called Charcot-Marie-Tooth neuropathy. Although few hereditary nerve diseases are fatal most cause lifelong disability. All cause weakness of the lower legs and later weakness and wasting of the muscles of the arm and hand. Affected individuals have difficulty running, frequent falls with gradually increasing disability eventually requiring splints and other walking aids. We propose to use the newly developed resources of the human genome project to locate the defective gene. In previous studies we have used these methods to locate the defective genes of 2 other hereditary diseases of nerve. In this study we propose to investigate a newly recognised form of CMT called intermediate CMT. Intermediate CMT has characteristics intermediate between the better known forms of CMT affecting the nerve itself (the axon) or the nerve insulation (the surrounding myelin sheath). The disorder may therefore affect both components of nerve. The affected gene may mediate communication between the nerve and its sheath. This research should give valuable insight into the mechanisms responsible for the maintenance of normal nerve. Finding the gene may therefore have relevance to many other diseases of nerve. This research is a systematic search and should lead to the abnormal gene causing the disease. Once the gene involved is known then an effective test will be developed. When we can test for the disease, we probably will find that the disorder is much more common than previously recognised. Knowledge of the function of this gene will lead to an understanding of how the disease develops and will eventually lead to effective treatments.Read moreRead less
Consequences Of Dynamin 2 PH Domain Dysfunction In Charcot-Marie-Tooth Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$665,267.00
Summary
Our team has just discovered a new gene mutation that causes Charcot-Marie-Tooth (CMT) disease. CMT is a clinically and genetically diverse family of human peripheral neuropathies. CMT neuropathy is the most common inherited peripheral neuropathy, affecting approximately 1 in 2500. It is the most common human genetic disorder known and is caused by fifty or more genes. CMT is of large economic significance since many of the affected individuals are on lifetime invalid pensions and require contin ....Our team has just discovered a new gene mutation that causes Charcot-Marie-Tooth (CMT) disease. CMT is a clinically and genetically diverse family of human peripheral neuropathies. CMT neuropathy is the most common inherited peripheral neuropathy, affecting approximately 1 in 2500. It is the most common human genetic disorder known and is caused by fifty or more genes. CMT is of large economic significance since many of the affected individuals are on lifetime invalid pensions and require continual medical and paramedical support. The new mutation we discovered is in a variant form of CMT and affects the protein dynamin 2, in an important region called the PH domain. The normal function of Dyn2 is to retrieve activated receptors for hormones and growth factors from the membrane of cells (caller receptor mediated endocytosis or RME) and it is also required for other functions like cell proliferation. The PH domain is the part of Dyn2 that allows it to move to the appropriate part of the cell when needed to do its job, but it is not known whether the mutation disrupts this function of Dyn2. Since Dyn2 has multiple cellular functions, it is not understood why it might cause the disease. Our goal is to understand why this mutation causes peripheral nerves to degenerate, by revealing which of dynamin's many functions are primarily affected. We expect to uncover a new concept in how RME links to neuronal degeneration. In previous studies we developed the first drugs that interact with PH domains. We will now fully develop these, and synthesise new drugs that interact with the PH domain, as candidates to effect some repair of the damaged PH domain. A better understanding of Dyn2 and endocytosis is crucial to understanding both CMT and ultimately for developing therapies.Read moreRead less
Mutation Analysis Of Novel Candidate Genes For X-linked Charcot Marie Tooth (CMTX3) Neuropathy.
Funder
National Health and Medical Research Council
Funding Amount
$191,434.00
Summary
Our goal is to explore how peripheral nerves degenerate by identifying the gene mutation causing an X linked form of Charcot Marie Tooth neuropathy (CMTX3). Using bioinformatic resources and state of the art gene mutation scanning we will complete characterisation and systematic screening of candidate genes and novel transcripts in the region. Discovery of this gene will provide a means to determine mechanisms causing axonal degeneration and lead to targeted therapeutic treatment strategies.
Neurotransmission In Functionally Distinct Vasodilator Pathways
Funder
National Health and Medical Research Council
Funding Amount
$809,934.00
Summary
A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in diameter, more blood flows through it to reach the appropriate ....A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in diameter, more blood flows through it to reach the appropriate organ. An important function of the nervous system is to control the flow of blood to different organs by changing the diameters of the blood vessels. One set of nerves decreases the diameter of the arteries, and another set of nerves increases the diameter. The nerves do this by releasing special combinations of chemicals when they get a message from the brain to do so. In this project we are especially interested in the nerves which increase blood flow to organs in the head and the pelvis. We will use a wide range of modern methods to find out how these nerves work. In some experiments, we will use sophisticated electrical equipment to measure just how the nerve cells controlling the diameter of the vessels respond to the instructions sent by the brain. In other experiments, we will find out which chemicals the nerves use to make the blood vessels increase in diameter. We also will discover how the various chemicals get released by the nerves at the right times, so that messages from the brain get to the blood vessels as efficiently as possible. One of the special parts of our project is that we will be able to observe directly the connections between the nerve cells and the blood vessels we are studying. Our results will be important for designing new drugs that could help people whose nerves are not working properly, such as in some patients with diabetes or vascular disease.Read moreRead less
IMMUNE-MEDIATED INFLAMMATION IN DORSAL ROOT GANGLIA AFTER PERIPHERAL NERVE INJURY AND IN SENSORY NEUROPATHIES
Funder
National Health and Medical Research Council
Funding Amount
$378,300.00
Summary
Damage to the nervous system can occur because of accidental or iatrogenic trauma, toxins, infection, metabolic disorders, and even normal ageing. The consequences can outweigh the direct effects of the injury. Almost all injury to the nervous system results in loss of nerve cells and consequently modified sensation and movement. Nerve damage may also be followed by sensory disturbances, ranging from tingling, numbness and abnormal temperature sensations to spontaneous pain, allodynia (painful s ....Damage to the nervous system can occur because of accidental or iatrogenic trauma, toxins, infection, metabolic disorders, and even normal ageing. The consequences can outweigh the direct effects of the injury. Almost all injury to the nervous system results in loss of nerve cells and consequently modified sensation and movement. Nerve damage may also be followed by sensory disturbances, ranging from tingling, numbness and abnormal temperature sensations to spontaneous pain, allodynia (painful sensations from light touch) or hyperalgesia (increased sensitivity to a damaging stimulus). Some of these symptoms are encountered in older people as they lose sensory neurones. The problems are chronic and most are intractable to drugs. This project will clarify how immune-mediated inflammation of dorsal root (sensory) ganglia (DRGs) contributes to these sequelae. Even the simplest form of neural damage following peripheral nerve injury can produce changes in regions of the nervous system far from the parts directly involved in the injury. Our recent work has described for the first time the involvement of the immune system in triggering changes in DRGs following transection of a distant peripheral nerve in rats. T-cell activation leads to invasion of macrophages and production of proinflammatory cytokines. These substances can activate sensory neurones and may be responsible for progressive neuronal death. Thus we have established a simple system in which we can evaluate the influx of T-cells and macrophages of different kinds into DRGs after injury and other insults. We intend to use this to define the sequence of cellular events involved in recruitment of immune cells and compare it with other experimental interventions known to produce a neuroimmune response in this system. This will identify whether the DRG is a special site for neuroimmune interactions and so should be a target for therapy.Read moreRead less
The Incidence And Predictors Of Foot Disease Hospitalisation
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Foot disease seems to be a much larger cause of hospitalisation than first thought. This research program aims to study for the first ever time the annual incidence of foot disease hospitalisation and develop models to predict which patients with foot disease are likely to be hospitalised or die. We believe this research will help clinicians, researchers and governments from around the world to measure, predict and prevent foot disease hospitalisation in their nations for the first time.
Developing Improved Management For Peripheral Artery Diseases
Funder
National Health and Medical Research Council
Funding Amount
$569,219.00
Summary
~1 million Australians have peripheral artery disease. The current application is for a Practitioner Fellowship to support my research aimed at improving care of artery disease. The aim of the work is to develop improved management approaches for patients with blocked and weakened arteries. This work is particularly important given the recognised management deficiencies for patients with artery disease and the relative little research being undertaken in this area.
The Mechanism Of Action Of IVIg In Inflammatory Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$452,141.00
Summary
Intravenous immunoglobulin (IVIg) is the major therapy used for the inflammatory neuropathies GBS, CIDP and for multifocal neuropathy. The cost of IVIg for these neuropathies in Australia is approximately 60 million dollars per year. As new indications for IVIg continue to be developed the resource becomes more valuable. We plan to explore the mechanism of action of IVIg with the aim of saving this precious resource and providing significant financial savings to the health service.