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Manipulation Of Intracellular Arginine Content In Endothelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$476,264.00
Summary
The lining layer of blood vessels (termed the 'endothelium') plays a vital role in the control of blood vessel function. Recently it has been shown that risk factors for heart and vascular disease (smoking, high blood pressure, high cholesterol and diabetes), heart attack and heart failure are associated with an abnormally functioning endothelium. In particular, the endothelium maintains blood vessels in a relaxed state, prevents the formation of blood clots (which may cause heart attack and str ....The lining layer of blood vessels (termed the 'endothelium') plays a vital role in the control of blood vessel function. Recently it has been shown that risk factors for heart and vascular disease (smoking, high blood pressure, high cholesterol and diabetes), heart attack and heart failure are associated with an abnormally functioning endothelium. In particular, the endothelium maintains blood vessels in a relaxed state, prevents the formation of blood clots (which may cause heart attack and stroke) and prevents the thickening of blood vessels. These important actions of the endothelium are explained by the production of nitric oxide (NO) a small chemical messenger that is derived from an amino acid, L-arginine, which circulates in blood. The amount of NO produced by endothelial cells is very dependent on the amount of arginine available, and this is determined by a careful balance between the amount of arginine taken (transported) into cells and the amount that is destroyed (metabolized) by an enzyme called arginase. Research undertaken in our laboratory is directed at understanding the important balance between arginine transport and arginase activity, as a basis for identifying new ways to prevent and treat cardiovascular disease. The current proposal describes a series of studies which will critically examine the importance of arginine transport and arginase activity, using transgenic models of over-activity and under-activity of these systems. Once established we will test the possibility that manipulating these systems may prevent atherosclerosis.Read moreRead less
Molecular Mechanisms Of Cardiac Function And Disease
Funder
National Health and Medical Research Council
Funding Amount
$8,213,642.00
Summary
Heart disease remains the leading cause of death in our society. Almost two million Australians suffer from the debilitating effects of heart disease and it is the leading cause of premature permanent disability in our workers. Heart defects are also the most common type of birth defect and the leading cause of deaths in infants dying from birth defects. Many of these problems can be attributed directly to defects in the development, repair and-or function of heart muscle and, at the cellular le ....Heart disease remains the leading cause of death in our society. Almost two million Australians suffer from the debilitating effects of heart disease and it is the leading cause of premature permanent disability in our workers. Heart defects are also the most common type of birth defect and the leading cause of deaths in infants dying from birth defects. Many of these problems can be attributed directly to defects in the development, repair and-or function of heart muscle and, at the cellular level, of heart muscle cells or cardiomyocytes. Understanding the cardiomyocyte as well as integrated heart development, biology, physiology and function, therefore, holds great promise for major advances in the prevention and treatment of contemporary heart diseases. This Program Grant brings together a unique team of interactive researchers with expertise in cardiovascular physiology, as well as developmental, cellular and molecular biology. The outcomes anticipated from new insights into heart biology that will result from the proposed studies, are the development of novel therapeutic approaches for the prevention and treatment of heart attacks and heart failure.Read moreRead less
FOXO Proteins And Protection From Cardiac Ischaemic Injury
Funder
National Health and Medical Research Council
Funding Amount
$354,375.00
Summary
Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the development of heart failure, a major cause of death and disability in western countries. Treatment with growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other tissues. For these reasons, it is necessary to establish ways ....Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the development of heart failure, a major cause of death and disability in western countries. Treatment with growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other tissues. For these reasons, it is necessary to establish ways to activate protective pathways in the heart without causing unwanted effects on other tissues. To this end, we have identified for the first time in the heart members of a newly described family of gene regulators that can cause cell death by increasing expression of cytotoxic factors. We showed that these FKHRor FOXO family members are regulated in the heart and that they are active in generating cytotoxic factors. We now plan to establish whether FOXO proteins are involved in causing cell death during heart attack and whether manipulating their activities can be cardioprotective.Read moreRead less
Altered Hepatic Pharmacokinetics As A Consequence Of Drug- And Disease-induced Changes In Hepatic Vascularity.
Funder
National Health and Medical Research Council
Funding Amount
$498,088.00
Summary
Many drugs are broken down by the liver or are removed from the liver out into the intestine by the bile, as well as being removed by the kidney and other organs. The effectiveness of the breakdown and removal by the liver depends both on whether the drug can get into the liver cells and on how well the enzymes in the liver are working. Cardiovascular and liver diseases and certain drugs can affect both of these processes. This work is concentrating on those processes which mainly affect the upt ....Many drugs are broken down by the liver or are removed from the liver out into the intestine by the bile, as well as being removed by the kidney and other organs. The effectiveness of the breakdown and removal by the liver depends both on whether the drug can get into the liver cells and on how well the enzymes in the liver are working. Cardiovascular and liver diseases and certain drugs can affect both of these processes. This work is concentrating on those processes which mainly affect the uptake process. The diseases of most interest are liver cirrhosis, fatty liver disease, atherosclerosis and chronic heart failure, all of which together are leading causes of death in Western countries. They are also associated with liver dysfunction due to effects on liver vessels. We have a poor understanding of how the effects of these diseases and a number of drugs on liver vessels affect the functioning of the liver, especially in terms of how they affect drug breakdown or removal of drugs. This project seeks to understand these effects and proposes a number of animal studies as well as human studies to provide insight. The drugs to be studied are those most commonly used in patients with cardiovascular and liver diseases, as one of our main goals is to provide better therapeutic management in these patients.Read moreRead less