Molecular Attributes And Physiological Significance Of Beta1L-adrenoceptors
Funder
National Health and Medical Research Council
Funding Amount
$754,353.00
Summary
Beta-blockers are used for the management of cardiovascular diseases including heart failure. We have discovered that one group of beta-blockers not only blocks the receptor but stimulates it. To explain this we hypothesize that human beta-adrenoceptors exist in two different 'states' , high and low. We are now determining whether 1. the low state causes progression of heart failure, 2. the molecular basis of the two states and 3. we can make new compounds to block the low state.
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
Hemokinin - A New Inflammatory Mediator In The Intestine.
Funder
National Health and Medical Research Council
Funding Amount
$382,768.00
Summary
Inflammatory bowel disease and acute diverticular disease are two serious and very costly inflammatory disorders of the bowel. Tachykinins are known to be causally involved in inflammation-induced bowel dysfunction. A new tachykinin peptide, hemokinin, is found in immune cells, but has not been studied at all in the intestine. In this project, we will study the effects of hemokinin on human bowel immune function. The study will provide essential information to formulate new treatments.
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.
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.
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune diseases. An agent that could block the effects of C5a could be very useful clinically. There is no such drug available as yet. We have developed powerful agents which specifically block C5a in laboratory tests on isolated cells and tissues, and now propose to test their effectiveness in rats in which the above human disease conditions are mimicked. Our preliminary results are very promising, and we will conduct further testing to determine the scope of the actions of the new drugs. One of our new agents is orally active in rats, and we will determine how the blood levels of the drug relate to its beneficial effects. We are also planning to develop agents that are more effective when given by mouth. The results could lead to a new type of anti-inflammatory drug for humans suffering from a variety of diseases that are poorly treatable at present.Read moreRead less
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.
Airway Virus Infection, Protease-activated Receptors And Microvascular Permeability
Funder
National Health and Medical Research Council
Funding Amount
$421,527.00
Summary
Asthma is an inflammatory airway disease which kills about 800 Australians each year and otherwise afflicts millions of children and adults in all age groups. Respiratory tract viral infections trigger inflammation and asthma. We believe that this is caused by the loss of naturally protective, bronchodilator and anti-inflammatory substances such as prostaglandin E2 and increased production of asthma promoting substances such as endothelins. Both of these substances are made by the epithelial lin ....Asthma is an inflammatory airway disease which kills about 800 Australians each year and otherwise afflicts millions of children and adults in all age groups. Respiratory tract viral infections trigger inflammation and asthma. We believe that this is caused by the loss of naturally protective, bronchodilator and anti-inflammatory substances such as prostaglandin E2 and increased production of asthma promoting substances such as endothelins. Both of these substances are made by the epithelial lining cells of the bronchi where viruses grow. This project will assess the influence of respiratory tract virus infection on epithelial mechanisms for the production of PGE2 and endothelins. Respiratory viral infections are accompanied by airway inflammation and thus by elevated microvascular permeability and oedema which exacerbates obstruction in asthma. We will measure airway microvascular permeability changes during viral infection and assess the protective effect of stimulating protease-activated receptors which increases PGE2 production. The impact of the PAR system on the integrity of microvascular tissue and on epithelial endothelin production has not been previously investigated. In addition, the influence of respiratory tract viral infection on PAR function in this system is also unknown, but is potentially of great importance to our understanding of the behaviour and regulation of this natural bronchoprotective pathway. This work may lead to the use of novel PAR activators as combined bronchodilator-anti-inflammatory therapies in asthma.Read moreRead less
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
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.