Probing Central And Peripheral Calcium Channel Sybtypes With Novel Omega Conotoxins
Funder
National Health and Medical Research Council
Funding Amount
$383,168.00
Summary
New toxins including omega-conotoxin CVID have been discovered from fish eating cone snails found on the Great Barrier Reef. These toxins discriminate between ion channel receptors on nerve cells that allow calcium ions to enter the cell and nerve transmission to continue. Of great importance is the fact that CVID specifically and potently blocks nerves that transmit pain responses. This project is involved with understanding the nolecular basis for this action with the goal of underpinning the ....New toxins including omega-conotoxin CVID have been discovered from fish eating cone snails found on the Great Barrier Reef. These toxins discriminate between ion channel receptors on nerve cells that allow calcium ions to enter the cell and nerve transmission to continue. Of great importance is the fact that CVID specifically and potently blocks nerves that transmit pain responses. This project is involved with understanding the nolecular basis for this action with the goal of underpinning the design of even more selective agents that will ameliorate pain while reducing side effects.Read moreRead less
Developing Novel Selective Glycine Receptor Potentiators As A Means To Control Pain.
Funder
National Health and Medical Research Council
Funding Amount
$552,647.00
Summary
It has been estimated that >3M Australians suffer from pain at a cost to the economy of >$34B, with chronic pain (persisting beyond 1-6 mths) accounting for ~half this burden. There is an urgent and compelling social and economic case for the development of safer and more effective pain therapeutics. This project takes inspiration from a new class of Australian marine natural products that selectively regulate a key pain pathway, and will optimize and develop these as a new class of pain d ....It has been estimated that >3M Australians suffer from pain at a cost to the economy of >$34B, with chronic pain (persisting beyond 1-6 mths) accounting for ~half this burden. There is an urgent and compelling social and economic case for the development of safer and more effective pain therapeutics. This project takes inspiration from a new class of Australian marine natural products that selectively regulate a key pain pathway, and will optimize and develop these as a new class of pain drug.Read moreRead less
The Structural Basis Of The Interaction Of Human Relaxins With Their Receptors.
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Human Gene 2 (H2) relaxin is a peptide hormone structurally related to insulin and has numerous biological actions related to its roles during pregnancy. It exerts these primarily by inducing the breakdown of collagen and the formation of new blood vessels while simultaneously stimulating tissue growth and inhibiting cell death. Its functions have led to several potential therapeutic roles for relaxin being explored. These include the treatment of fibrotic disorders and peripheral vascular disea ....Human Gene 2 (H2) relaxin is a peptide hormone structurally related to insulin and has numerous biological actions related to its roles during pregnancy. It exerts these primarily by inducing the breakdown of collagen and the formation of new blood vessels while simultaneously stimulating tissue growth and inhibiting cell death. Its functions have led to several potential therapeutic roles for relaxin being explored. These include the treatment of fibrotic disorders and peripheral vascular disease. H2 relaxin is the principal expression product in vivo and has been shown to exert a wide range of physiological responses beyond those normally associated with pregnancy. We have recently discovered another human - H3 - relaxin that is expressed primarily in the brain which strongly suggests a neuropeptide role. Surprisingly, H2 and 3 relaxins each act via different G-protein coupled receptors. We will perform detailed structure-function studies to determine how these relaxins impart their specific biological actions. Modern chemical synthesis protocols will be used to prepare each of these complex peptides in adequate quantities for detailed secondary and tertiary structural study. Analogues containing modified residues and global domains will be prepared and assayed for characteristic relaxin agonist and antagonist activity. Sophisticated biomolecular interaction analyses will be used to identify differences in receptor binding regions for the two relaxins. The results, together with those obtained by three-dimensional structural analysis using NMR spectroscopy, will allow us to ultimately define the key features of the H2 and 3 hormones that are responsible for selective receptor binding and specific relaxin activity. We will then be able to design smaller, more stable, orally active relaxin mimetics. Such compounds will have great potential for therapeutic application in the treatment of fibrosis or as biological and pharmacological probes of relaxin action.Read moreRead less
The Structural Basis Of The Interaction Of Human Relaxins With Their Receptors.
Funder
National Health and Medical Research Council
Funding Amount
$573,807.00
Summary
Relaxin is a peptide that is involved in the regulation of the birth process. It has considerable promise as an anti-fibrotic agent. Recently, another relaxin-like peptide, relaxin-3, was identified and shown to be brain-specific. It modulates the stress response and appetite. Both relaxins act upon different receptors to elicit their biological effects. To exploit their clinical potential, we will determine how these peptides selectively bind and ativate their individual receptors.
The Pharmacology And Physiology Of GABA-C Receptors
Funder
National Health and Medical Research Council
Funding Amount
$481,980.00
Summary
GABA is one of the most important chemicals in the brain. GABA and its associated receptors (GABA receptors) work together to keep the balance between neuronal excitation and inhibition which is required for normal brain function. There are three types of GABA receptors called GABA-A, GABA-B and GABA-C receptors. Chemicals acting at these receptors may be therapeutically useful in treating neurological probles such as epilepsy, anxiety, depression and memory-related disorders associated with Alz ....GABA is one of the most important chemicals in the brain. GABA and its associated receptors (GABA receptors) work together to keep the balance between neuronal excitation and inhibition which is required for normal brain function. There are three types of GABA receptors called GABA-A, GABA-B and GABA-C receptors. Chemicals acting at these receptors may be therapeutically useful in treating neurological probles such as epilepsy, anxiety, depression and memory-related disorders associated with Alzheimer's disease and schizophrenia. GABA-A and GABA-C receptors are members of the ligand-gated ion channel super family in which the ion channel forms an intergral and central part of the receptor. In response to GABA, the channel opens and chloride ions flow through the channel. This causes an inhibitory action i.e. the cell reduces its rate of firing. This project aims to study GABA-C receptors by investigating what proteins make up the ion channel, by studying the actions of a range of chemicals that have specific effects at these receptors and by identifying amino acids that are important for normal channel function. New chemicals identified in our studies will provide leads for the design and development of new therapeutic agents acting on the brain.Read moreRead less