Activation Mechanisms Of The Hypoxia Inducible Factor-1a (HIF-1a) And The HIF-Like-Factor
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
A continual supply of oxygen is essential for normal functioning of the human body. When oxygen levels become limiting, the body attempts to rectify the situation by increasing the number of oxygen carrying red blood cells and promoting development of new blood vessels to increase the blood supply to tissues. Cells also adapt by altering their internal biochemistry and metabolism to decrease energy needs. These changes are the result of a genetic reprogramming within the cells. A major question ....A continual supply of oxygen is essential for normal functioning of the human body. When oxygen levels become limiting, the body attempts to rectify the situation by increasing the number of oxygen carrying red blood cells and promoting development of new blood vessels to increase the blood supply to tissues. Cells also adapt by altering their internal biochemistry and metabolism to decrease energy needs. These changes are the result of a genetic reprogramming within the cells. A major question is how the cells sense they are in a low oxygen environment and by what mechanisms they initiate genetic reprogramming. We are studying two proteins which have the ability to alter activity of genes when cells are stressed by hypoxia (low oxygen), and seek to discover how the proteins switch from latent forms to active forms in response to hypoxia. A greater understanding of the molecular mechanisms involved in the cellular hypoxic response is important to the development of new therapeutics for disease states involving disrupted oxygen flow (eg heart attack and stroke). Drugs which would block the hypoxic induced development of blood vessels could also be extremely beneficial in cancer treatment, as blocking blood supply to growing tumours can result in their starvation and shrinkage.Read moreRead less
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
I am a cell-molecular biologist studying the role and regulation of the plasminogen activating (fibrinolytic) system in health and disease. My recent studies have defined a novel role for tissue-type plasminogen activator in the central nervous system and
Mimicking Protein Surfaces With Cyclic Peptides: W-conotoxin GVIA Mimics As Novel Analgesic And Neuroprotective Agents
Funder
National Health and Medical Research Council
Funding Amount
$216,412.00
Summary
The omega-conotoxins are small polypeptides (of around 25 residues) cross-linked by three disulfide bonds. At least two of these, omega-conotoxins GVIA and MVIIA, are potent and selective blockers of N-type voltage-gated calcium channels. Administered to the CNS via an intrathecal catheter, MVIIA and GVIA are analgesic in acute, chronic and neuropathic pain models, and protective following ischaemia-induced neuronal injury, such as occurs following stroke. They do not suffer from the development ....The omega-conotoxins are small polypeptides (of around 25 residues) cross-linked by three disulfide bonds. At least two of these, omega-conotoxins GVIA and MVIIA, are potent and selective blockers of N-type voltage-gated calcium channels. Administered to the CNS via an intrathecal catheter, MVIIA and GVIA are analgesic in acute, chronic and neuropathic pain models, and protective following ischaemia-induced neuronal injury, such as occurs following stroke. They do not suffer from the development of tolerance, in contrast with the opioids, such as morphine, which lose their analgesic potency over time and have undesirable side effects. We have determined the three-dimensional structure of GVIA and mapped onto that structure its calcium channel binding surface. This information is a starting point for the structure-based design of truncated and stabilised peptidic analogues of GVIA, which should have several advantages over the native polypeptides as candidates for the treatment of chronic pain and ischaemia-induced neuronal damage. In the course of this work we shall also generate a range of libraries of experimentally determined and predicted structures based on small, cyclic peptides. These libraries will be valuable tools for mimicking key functional regions of protein surfaces in small molecules that are easily (and cheaply) synthesised and have potentially favourable bioavailability. Thus, this project will also increase our understanding of the attributes of small cyclic peptides as mimics of functionally important protein surfaces and provide valuable tools for the design and evaluation of such peptides.Read moreRead less