The Role Of Netrin-DCC In The Development Of The Corpus Callosum
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with ove ....During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with over 50 different human congenital syndromes. Thus understanding how the genes and molecules involved in the formation of the corpus callosum function in normal development can provide the basis for our understanding of what goes wrong in ACC. In this proposal we will investigate the role of the axon guidance molecule Netrin1, and its receptor DCC, in development of the corpus callosum in both a mouse model and in humans with malformations of the corpus callosum. Although Netrin1-DCC signalling has traditionally been associated with mechanisms of axon guidance, we hypothesize that these molecules may play a different role, specifically in cellular adhesion and ultimately in the fusion of the two cerebral hemispheres, in a manner that allows the corpus callosum to form. A second role for Netrin1-DCC signalling may be in the guidance of these axons once the midline has fused correctly and we investigate this in Aim 2 of the proposal. Finally, we are collaborating with a paediatric neurologist at UCSF, who has identified several mutations in the DCC gene in patients with ACC. In Aim 3 we test whether these mutations disrupt the function of DCC in callosal axon pathfinding. Understanding how these genes function during development of the brain and how their function may be altered in ACC is crucial to providing a proper diagnosis and prognosis for these patients. Ultimately, understanding more about how these genes function could also lead to prevention of these disorders.Read moreRead less
Modulating Beta-amyloid Aggregation And Toxicity With Natural Metal-binding Proteins
Funder
National Health and Medical Research Council
Funding Amount
$399,243.00
Summary
Alzheimer's disease (AD) is a devastating disorder that afflicts millions of people worldwide. It is well established that the small peptide beta-amyloid, has a direct and important role in the development of AD. This project will investigate the ability of a small naturally occurring metal-binding protein to block the toxic actions of beta-amyloid.
Supraspinal Neural Adaptations In The Transition From Acute Injury To Chronic Pain And Disability
Funder
National Health and Medical Research Council
Funding Amount
$429,360.00
Summary
Although there have been significant clinical advances in the management of injury and the control of acute pain following tauma, many people still develop disabling conditions of chronic pain. Chronic pain and disability occurs even though the acute signs of trauma have subsided and injuries have healed. People with chronic pain conditions not only experience ongoing changes in sensation (ie., most commonly lowered thresholds for pain, touch evoked pain and spontaneous pain), they also endure a ....Although there have been significant clinical advances in the management of injury and the control of acute pain following tauma, many people still develop disabling conditions of chronic pain. Chronic pain and disability occurs even though the acute signs of trauma have subsided and injuries have healed. People with chronic pain conditions not only experience ongoing changes in sensation (ie., most commonly lowered thresholds for pain, touch evoked pain and spontaneous pain), they also endure a number of disabilities for example disrupted family and social relations, disturbed sleep, loss of appetite, weight changes, loss of sex drive, changes in menstrual cycle, the inability to cope with stressors, and often moderate to severe anxiety and depression. The proposed research aims to (i) identify changes in brain circuits which are responsible for producing these patterns of pain and disability following injury and (ii) attempts to selectively reverse some of these disabilities by reversing the brain changes. The results of this study will offer for the first time a rational basis for improving the outcomes of injury and pain management in the acute phase of trauma, by identifying and reversing the critical changes which predict the advent of the state state of chronic pain and disability.Read moreRead less
Excitatory Synaptic Circuitry And Plasticity In The Amygdala.
Funder
National Health and Medical Research Council
Funding Amount
$405,750.00
Summary
The amygdala is a key structure in the neuronal circuitry that underlies the analysis of emotional information. In particular this structure plays a major role in the processing of fear-related information. Disorders of the processing and storage of such information are thought to be the major underlying cause of mental disorders such as panic attacks, anxiety and post traumatic stress disorder. Understanding the physiology of this structure and the ways in which this can change in response to v ....The amygdala is a key structure in the neuronal circuitry that underlies the analysis of emotional information. In particular this structure plays a major role in the processing of fear-related information. Disorders of the processing and storage of such information are thought to be the major underlying cause of mental disorders such as panic attacks, anxiety and post traumatic stress disorder. Understanding the physiology of this structure and the ways in which this can change in response to various stimuli is necessary for the development of rational therapies that target the amygdala.Read moreRead less
Alzheimer's Disease And Related Disorders: Mechanism Of Tau Pathology In Established And Novel Transgenic Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$423,017.00
Summary
Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We wer ....Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We were the first to establish a transgenic animal model of pre-tangles and, together with Dr. Hutton's laboratory, of NFT formation. We could further show that injections of beta-amyloid into brains of our tau mutant mice enhanced the NFT pathology in these mice. By Functional Genomics we identied genes and proteins, which are induced by tau expression. The specific aim of this proposal is to determine whether oxidative stress enhances the tau pathology in our tau mutant mice and whether distinct brain areas are particularly susceptible to this kind of stress. The reason for addressing this question is twofold: On the one hand, we have found in our mice that reactive oxygen species are increased, secondly it is known that some brain areas in the AD brain are degenerating, whereas others are not. A second aim is to develop novel tau transgenic models where individual interactions of tau with cellular proteins are disturbed. Finally, we want to determine whether the two kinases BMX and FAK and the phosphatase PPV regulate tau phosphorylation in vivo. Together, we hope that our efforts lead to a better understanding of the pathogenic mechanisms in AD and related disorders. As pathocascades are likely to be shared between a range of diseases, these findings may also contribute to other fields of research, such as Parkinson's disease. Ultimately, these efforts will assist in the development of a safe treatment of AD.Read moreRead less