A Novel Knockin Model To Test The Role Of Nicotine Acting On Alpha4 Acetylcholine Receptors In Complex Behaviours
Funder
National Health and Medical Research Council
Funding Amount
$581,315.00
Summary
Cigarette smoking is the single largest preventable cause of death and disease in Australia and worldwide. Nicotine contained in tobacco products acts on brain nicotine receptors, which plays an intrinsic role in addiction. One type of receptor for nicotine found in regions of the brain associated with drug-seeking behaviour is called alpha4 nicotinic receptors. We have made a mouse with a mutation in this nicotine receptor to study nicotine addiction and anxiety.
Professor Lewis is a molecular pharmacologist interested in discovering new venom peptides and ciguatoxins and determining how they interact with the membrane proteins they target using advanced biochemical and spectroscopic methods. Peptides of interest are then modified to improve potency and selectivity. Those with appropriate properties are patented and developed for clinical applications using approaches successfully applied to Xen2174, a conopeptide analogue I co-discovered that is now in ....Professor Lewis is a molecular pharmacologist interested in discovering new venom peptides and ciguatoxins and determining how they interact with the membrane proteins they target using advanced biochemical and spectroscopic methods. Peptides of interest are then modified to improve potency and selectivity. Those with appropriate properties are patented and developed for clinical applications using approaches successfully applied to Xen2174, a conopeptide analogue I co-discovered that is now in Phase II clinical trials for severe pain.Read moreRead less
Structural And Functional Consequences Of A Human Nicotinic Receptor Mutation
Funder
National Health and Medical Research Council
Funding Amount
$112,809.00
Summary
Identification of the defective gene underlying a particular form of inherited epilepsy in man, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), now provides the first opportunity to study the basic mechanisms of an inherited epilepsy in man. The responsible mutations affect a subunit of the nicotinic acetylcholine receptor. In this research project, quantitative methods of imaging the brain will be used bridge the gap in understanding which lies between the molecular defect and the ....Identification of the defective gene underlying a particular form of inherited epilepsy in man, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), now provides the first opportunity to study the basic mechanisms of an inherited epilepsy in man. The responsible mutations affect a subunit of the nicotinic acetylcholine receptor. In this research project, quantitative methods of imaging the brain will be used bridge the gap in understanding which lies between the molecular defect and the clinical manifestations of ADNFLE. Involvement of a system of nerve pathways, the mesocortical dopaminergic system, is postulated to explain the preferential susceptibility of the frontal lobe to seizures in ADNFLE. Positron emission tomography will be used to examine changes in neurotransmitter release in the frontal lobe. The molecular defect in ADNFLE also provides a unique opportunity to examine the role of the nicotinic receptor in the development of the human brain and in important aspects of human cognition. Statistical mapping of anatomical variability and high resolution magnetic resonance scans will be used to detect alterations in the anatomical structure of the mesial frontal lobe. Evidence of deficient nicotinic receptor-mediated cognitive effects in ADNFLE will be sought using a battery of psychological tests shown to be sensitive to the effects of nicotine.Read moreRead less
Protein Partners Of Rapsyn That Regulate Acetylcholine Receptor Clustering
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
Spinal nerves control our limb muscles by releasing chemical signals directly onto the surface of muscle fibres that they contact. These chemical signalling contacts are called synapses. They are like the synapses between nerve cells in our brains but easier to study, meaning that we can make more rapid progress in understanding how synapses work. The sensor receptors for chemical signals at the nerve-to-muscle synapse are held in place on the muscle fibre surface by a protein called rapsyn. In ....Spinal nerves control our limb muscles by releasing chemical signals directly onto the surface of muscle fibres that they contact. These chemical signalling contacts are called synapses. They are like the synapses between nerve cells in our brains but easier to study, meaning that we can make more rapid progress in understanding how synapses work. The sensor receptors for chemical signals at the nerve-to-muscle synapse are held in place on the muscle fibre surface by a protein called rapsyn. In turn, rapsyn must be organized by other chemical signals from the nerve, but we don't know exactly how this happens. When the receptors become disorganized at the synapse, in diseases such as Myasthenia Gravis, we lose control of our muscles. This project will employ newly developing techniques of proteomics and genomics to identify new proteins that bind to rapsyn and to test how they work to organize receptors at the synapse. By identifying the proteins that control rapsyn we may be able to develop new treatments for Myasthenia Gravis that restore the function of the synapse with less side effects than current therapies.Read moreRead less