Heme-oxidised Soluble Guanylyl Cyclase, A Mechanism-based Target For Vascular Diagnostics And Vasoprotective Therapy
Funder
National Health and Medical Research Council
Funding Amount
$524,456.00
Summary
Nitric oxide is produced in the inner lining of blood vessels and maintains blood flow via binding to a specific protein, sGC. In disease, sGC is defective and can be targeted by a novel group of drugs which are more active in diseased versus normal blood vessels. This project will examine the use of these drugs as markers of cardiovascular disease and in the treatment of high cholesterol and may lead to the development of new diagnostic tools and therapies for vascular complications.
MECHANISMS OF CEREBROVASCULAR REGULATION IN HEALTH AND DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$216,430.00
Summary
Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent and significant research at the basic level to better understand mechanisms of normal, and then abnormal, regulation of cerebral artery function. The project will examine the importance of a novel mechanism in regulating brain blood flow by affecting the ....Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent and significant research at the basic level to better understand mechanisms of normal, and then abnormal, regulation of cerebral artery function. The project will examine the importance of a novel mechanism in regulating brain blood flow by affecting the degree of opening of the cerebral arteries. This mechanism involves activation of an enzyme, Rho-kinase, which is present in the wall of blood vessels. The applicants believe that this process plays an important role in the normal, healthy regulation of blood supply to the brain. Moreover, there are strong reasons for us to speculate that the function of this enzyme is abnormally high in two disease states that are associated with an increased risk of stroke - high blood pressure and subarachnoid haemorrhage. We will employ a variety of techniques to assess the importance of Rho-kinase in cerebral artery function in the living body, and also in isolated segments of artery. The results are expected to provide major new insight into mechanisms that regulate brain blood flow, and the knowledge gained here may lead to better therapies to prevent or treat stroke.Read moreRead less
Targeting Arginase In Peripheral Arterial Occlusive Disease
Funder
National Health and Medical Research Council
Funding Amount
$243,945.00
Summary
Peripheral artery occlusive disease causes narrowing of large peripheral blood vessels which can result in severe pain, gangrene and stroke. Its prevalence is steadily increasing in western countries. This proposal aims to characterize the role of an enzyme (arginase) in PAOD and determine whether it may be a new drug target for treatment of this disease.
Selectivity And Mode Of Action Of Rho-conopeptide TIA: A Novel Inhibitor Of Alpha1-adrenoceptors.
Funder
National Health and Medical Research Council
Funding Amount
$399,300.00
Summary
A major obstacle to the development of safer and more effective treatments for cardivascular diseases and benign prostatic hyperplasia is the inability to find small molecules with sufficient specificity to be safe and effective. The applicant team brings together a unique set of complementary research interests and skills in using conotoxins to define, at the molecular level, how rho-conotoxins act at the alpha1-adrenoceptor, a major drug target for cardiovascualr and related diseases. Rho-cono ....A major obstacle to the development of safer and more effective treatments for cardivascular diseases and benign prostatic hyperplasia is the inability to find small molecules with sufficient specificity to be safe and effective. The applicant team brings together a unique set of complementary research interests and skills in using conotoxins to define, at the molecular level, how rho-conotoxins act at the alpha1-adrenoceptor, a major drug target for cardiovascualr and related diseases. Rho-conotoxins are novel peptide inhibitors of the alpha1-adrenoceptor that appear to act at an undescribed allosteric site. This Project will use rho-conotoxins and analogues to characterise structurally and functionally how and where this class of conopepides act. The structure activity relationship for rho-conotoxins will be established to guide the development of subtype specific inhibitors. Pairwise interactins between the alpha1-adrenoceptorand TIA will be used to dock TIA onto a homolgy model of the alpha1-adrenoceptor. The long-term goal of the project is to develop new and safer treatments for cardiovascular and related disorders.Read moreRead less
Modulation Of Asthmatic Airway Inflammation By Activation Of Epithelial Proteinase Activated Receptors
Funder
National Health and Medical Research Council
Funding Amount
$188,912.00
Summary
Children and adults feel the symptoms of asthma because their airways close up too easily. We have discovered a new mechanism that the healthy lung uses to keep airways open. The epithelial cells which line the airway release an enzyme that cuts of a small part of another protein, called a PAR receptor, that sits on the same cell. When this happens the epithelial cell releases relaxing substances from their lower surface. The relaxing substances keep the airways open. This grant application is d ....Children and adults feel the symptoms of asthma because their airways close up too easily. We have discovered a new mechanism that the healthy lung uses to keep airways open. The epithelial cells which line the airway release an enzyme that cuts of a small part of another protein, called a PAR receptor, that sits on the same cell. When this happens the epithelial cell releases relaxing substances from their lower surface. The relaxing substances keep the airways open. This grant application is designed to test whether the relaxing system also stops the airways from developing inflammation. If the relaxing system does this we will be able to use the knowlege we have that lets us activate the PAR receptors artificially to design new types of drugs. These drugs would be better than existing asthma drugs because they would prevent inflammation and relax the airways at the same time. These drugs could also be useful in other lung diseases such as chronic bronchitis.Read moreRead less
Studies Of Metabolites Of Synthetic Flavonols For The Treatment Of Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$207,440.00
Summary
Cardiovascular disease, including heart attack and stroke, is the leading killer of Australians. A promising new drug, NP202, can reduce the amount of tissue damaged from a heart attack; however, its mechanism of action remains obscure. NP202 is metabolized to a range of compounds, one of which is partly responsible for its beneficial effects. In this project we will identify other metabolites of NP202 and characterize their biological activity to gain insight into its mechanism of action.
Understanding Local And Regional Determinants Of EDHF And NO Dysfunction In Resistance Arteries In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$771,295.00
Summary
Diabetes is a serious and increasing health burden worldwide. Most of the sickness and death associated is due to complications arising in the blood vessels. The inner lining of blood vessels in small arteries uses several different mechanisms to ensure proper blood flow, and in diabetes these are impaired. This study will reveal the cellular mechanisms involved and identify pathways for therapeutic intervention to alleviate the debilitating effects of small artery disease.
The In Vivo And In Vitro Biology Of The Novel Intracellular Ion Channel CLIC1 (NCC27)
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Ion channels are complex proteins that regulate the transports of salts, and essential cell function. We have recently cloned a new ion channel, CLIC1, unique in its location on the nuclear membrane as well as other sites. The function of this channel is uncertain, although we have suggested its association with cell growth and inflammation. We propose to investigate the function of CLIC1, dominantly based on gene knockout animals, in which the CLIC1 gene has been deleted.