The Role Of Connexins In Blood Pressure Regulation: Use Of A Conditional Gene Expression System
Funder
National Health and Medical Research Council
Funding Amount
$583,767.00
Summary
Cell coupling through gap junctions is said to play an important role in regulating blood flow and blood pressure. However data obtained from mice, in which specific gap junctions are deleted, may be compromised by compensatory changes in other junctions. We have validated a new method for rapidly and reversibly altering gap junctions in adult mice with oral sugar. This technique will enable us to directly determine whether interference with cell coupling affects blood flow and blood pressure.
Myoendothelial Gap Junctions: Their Composition And Role In Vasodilator Responses Attributed To EDHF
Funder
National Health and Medical Research Council
Funding Amount
$282,750.00
Summary
Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes, is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under normal conditions, the endothelium is more important ....Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes, is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under normal conditions, the endothelium is more important as a source of relaxing factors, while under hypertensive conditions, the balance is shifted in favour of the release of constricting factors. Thus, restoration of the vasodilatory function of the endothelium is seen as an important new therapeutic target in the treatment of vascular disorders. Present data suggests that the action of one of the major endothelial derived vasodilatory factors, the so-called endothelium-derived hyperpolarizing factor, EDHF, requires the presence of particular structures within the vascular wall, but little is known about the molecules of which they are comprised. We have identified two unique situations, during development and during hypertension, when these structures are present in vessels in which they are absent in normal adults. We will use gene microarrays to identify the specific molecules involved in these structures and use physiological studies to test the role of these proteins and structures in vasodilatory responses. The results of these studies may identify new targets for therapeutic intervention to restore the action of EDHF in hypertension.Read moreRead less
Preclinical Assessment Of Gene Therapy For Ventricular Arrhythmia
Funder
National Health and Medical Research Council
Funding Amount
$801,079.00
Summary
Up to 10% of patients are at risk of sudden death following myocardial infarction. Current treatment and preventative initiatives have their limits and are not without risk. In this proposal we will continue to develop an exciting new treatment approach using gene therapy technology. We will attempt to overcome some of the barriers for human application of this technology and pave the way for early phase clinical trials.
The Role Of Connexin40 In The Pathogenesis Of Atrial Fibrillation Probed By Targeted In Vivo Gene Transfer
Funder
National Health and Medical Research Council
Funding Amount
$529,015.00
Summary
Atrial fibrillation (AF) is a fast and irregular heart rhythm that can predispose sufferers to heart failure and stroke. AF occurs as the result of abnormal electrical conduction in the upper heart chambers. We have found that a protein called Cx40 causes abnormal conduction in heart cells when grown in culture. The aim of this research is to see if AF occurs when Cx40 is increased and prevented when Cx40 is decreased in an AF animal model, potentially defining Cx40 as new therapeutic target.
Characterisation Of A New Family Of Proteins Involved In Cell Signalling, RNA Metabolism And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
We have discovered a novel RNA-binding protein (G3BP-2) that is involved in responding to external signals, such as growth factors, at the level of gene expression. Other RNA-binding proteins belonging to the same broad group of proteins are responsible for a host of disease states in mammals including mental retardation, myotonic dystrophy, Huntington?s disease and cancers. Considering the wealth of knowledge accumulated that implicates these proteins to human dysfunction surprisingly few of th ....We have discovered a novel RNA-binding protein (G3BP-2) that is involved in responding to external signals, such as growth factors, at the level of gene expression. Other RNA-binding proteins belonging to the same broad group of proteins are responsible for a host of disease states in mammals including mental retardation, myotonic dystrophy, Huntington?s disease and cancers. Considering the wealth of knowledge accumulated that implicates these proteins to human dysfunction surprisingly few of these RNA-binding proteins have been identified. We have shown that the novel protein discovered in our laboratory is perturbed in cancer and we are interested in characterising its putative role in cancer. The results established in our laboratory so far would indicate that generally, G3BP-2 is expressed in normal tissue and it expression changes in some cancers studied so far. Considering that G3BP-2 lies in a pathway known to be involved in cancer progression it is important to understand what effects the inappropriate expression of G3BP-2 may have on cancer progression and survival. This project is designed to characterise what signals the cell uses to control these proteins and in turn which genes these may effect. In this way we may be able to determine how external signals may effect tumour progression and on what genes this influence is expressed. It would be hoped that this project would increase our understanding of cancer and potentially lead to new diagnostic reagents and therapies in the treatment of cancer.Read moreRead less
A Novel Mechanism For Intestinal Propulsion: Transit Without Neurons Or Pacemakers
Funder
National Health and Medical Research Council
Funding Amount
$256,973.00
Summary
A significant complication of premature births is that the mechanisms that regulate normal intestinal movements have not yet fully developed. We have recently identified a novel pattern of contraction that is seen predominantly in the colon of mice that have not yet developed either the normal nerve circuits that control gut movement and also lack the pacemaker cells that are intrinsic to the muscle coat. This motor pattern appears to be responsible for the movement of gut content during the dev ....A significant complication of premature births is that the mechanisms that regulate normal intestinal movements have not yet fully developed. We have recently identified a novel pattern of contraction that is seen predominantly in the colon of mice that have not yet developed either the normal nerve circuits that control gut movement and also lack the pacemaker cells that are intrinsic to the muscle coat. This motor pattern appears to be responsible for the movement of gut content during the development and maturation of the nerve circuits that regulate this process in more adult animals. However, the mechanisms responsible for this process have not been identified. This project is directed at identifying these mechanismsRead moreRead less