Cellular Metabolism And Signalling In Cardiac Development And Congenital Disease
Funder
National Health and Medical Research Council
Funding Amount
$151,061.00
Summary
This project aims to investigate how the paediatric heart responds to oxidative cellular stresses during cardiac development, surgical stress and congenital heart disease. Pre-surgical interventions aims at improving cardiac function following surgery will be examined, with cellular models being used to determine molecular pathways of cardioprotection, as well as testing agents which may limit cellular damage under surgical stress and disease.
Defining The Roles Of NADPH Oxidases In Vascular Remodelling And Arterial Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$401,523.00
Summary
Hypertension (high blood pressure) is a major risk factor for cardiovascular diseases such as heart attacks, heart failure and stroke - the major causes of death world-wide and a huge burden on the Australian health care budget. Oxidative stress, resulting from an imbalance in the production and removal of toxic molecules called free radicals within the blood vessel wall, is a key player in the initiation and progression of these disorders. In the early stages of hypertension, production of free ....Hypertension (high blood pressure) is a major risk factor for cardiovascular diseases such as heart attacks, heart failure and stroke - the major causes of death world-wide and a huge burden on the Australian health care budget. Oxidative stress, resulting from an imbalance in the production and removal of toxic molecules called free radicals within the blood vessel wall, is a key player in the initiation and progression of these disorders. In the early stages of hypertension, production of free radicals only just outweighs their removal, resulting in a mild oxidative stress. However, this is enough to trigger a cascade of downstream events leading to activation of other, normally dormant, free radical generating systems. At these excessive levels, free radicals attack the cells of the artery wall leading to blood vessel dysfunction and ultimately cardiovascular disease. A major source of free radicals in the blood vessel wall are a family of enzymes called NADPH oxidases. It is our hypothesis that upregulation of onr of these enzymes in the early stages of hypertension is the initial trigger for many of the downstream effects that ultimately lead to cardiovascular disease. Our group is uniquely poised to test this hypothesis as we are the only laboratory in the world with access to three different strains of genetically modified mice, each lacking one of the three known isoforms of NADPH oxidase. Identification of the specific isoform of NADPH oxidase involved in free radical production in blood vessels is a critical first step in developing drugs that block vascular free radical production and so remove the molecular link between hypertension and major cardiovascular events.Read moreRead less
Nitroso-redox Imbalance In Glucocorticoid-induced Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$341,210.00
Summary
High blood pressure (hypertension) affects 20-30 % of Australian adults and in about 90-95 % of these individuals the hypertension is considered essential (cause unknown). Globally, it is the number 1 risk factor for death, and number 3 for disability (World Health Report 2002). The major consequences of hypertension are heart attack and stroke. Glucocorticoid (adrenal steroid hormone) induced hypertension and consequent cardiovascular morbidity-mortality is an important clinical problem. Althou ....High blood pressure (hypertension) affects 20-30 % of Australian adults and in about 90-95 % of these individuals the hypertension is considered essential (cause unknown). Globally, it is the number 1 risk factor for death, and number 3 for disability (World Health Report 2002). The major consequences of hypertension are heart attack and stroke. Glucocorticoid (adrenal steroid hormone) induced hypertension and consequent cardiovascular morbidity-mortality is an important clinical problem. Although naturally occurring glucocorticoid (GC) hypertension (Cushing's syndrome) is relatively rare, synthetic GC are widely used in clinical practice (in numerous inflammatory and autoimmune diseases and transplantation) and produce substantial cardiovascular morbidity and mortality. Further, abnormal GC breakdown (metabolism) and sensitivity to GC have been reported in around a third of essential hypertensive patients. We therefore need to understand how GC raise blood pressure and whether we can prevent and-or reverse these blood pressure raising effects. In the proposed studies, we will explore the role of relative deficiency of blood vessel dilating nitric oxide and nitric oxide inhibition by excess superoxide (nitroso-redox imbalance) in the genesis of GC hypertension. Further, we will identify agents known to be suitable for clinical use which are effective in preventing-reversing GC hypertension in the rat and are thus appropriate for clinical trials to prevent-reverse GC hypertension in humans. These studies will help answer the question of how GC raises blood pressure so that safer steroids can be designed, as well as identify agents that can potentially prevent or treat GC hypertension in humans.Read moreRead less
Lipotoxicity, Mitochondrial Dysfunction And The Pathogenesis Of Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$454,358.00
Summary
Heart failure (HF) is the most common basis for hospitalisation or cardiac death despite improved treatment options. Impaired energy generation within heart muscle is important in causing HF, but little is known about this process. I plan to investigate the effects of fatty acid overload, as occurs in obesity and/or diabetics, on cardiac energy generation. Then, I'll explore the benefits of limiting fatty acids during heart surgery, in order to help in understanding the causes of HF, and the ben ....Heart failure (HF) is the most common basis for hospitalisation or cardiac death despite improved treatment options. Impaired energy generation within heart muscle is important in causing HF, but little is known about this process. I plan to investigate the effects of fatty acid overload, as occurs in obesity and/or diabetics, on cardiac energy generation. Then, I'll explore the benefits of limiting fatty acids during heart surgery, in order to help in understanding the causes of HF, and the benefits of new, energy-conserving treatmentsRead moreRead less
Nox Isoforms And Chemokine Receptors As Therapeutic Targets In Vascular Disease And Stroke
Funder
National Health and Medical Research Council
Funding Amount
$727,758.00
Summary
I am a pharmacologist (a scientist who studies drugs and how they work) trying to find new drugs to treat heart attacks and strokes. I seek to understand the pathways that cause white blood cells and free radicals to accumulate in the walls of arteries in patients with high blood pressure and high cholesterol, and in the brain after stroke. I will then test whether these pathways can be blocked with novel chemical compounds that may eventually be developed into drugs suitable for use in humans.
Role Of The Paraventricular Hypothalamus In Angiotensin Induced Neurogenic Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$447,014.00
Summary
Hormones released from the kidney are important for setting the level of blood pressure. We have discovered that very low levels of the peptide angiotensin in the blood also leads to activation of specific parts of the brain that drive to increase the nervous system activity to blood vessels and therefore increases blood pressure further. This study will explore the chemical signals in the brain mediating this increase in blood pressure.
B1a B Cells: Atheroprotective Mechanisms And Therapeutic Application
Funder
National Health and Medical Research Council
Funding Amount
$547,180.00
Summary
Atherosclerosis-related heart attacks and strokes remain leading causes of global deaths despite use of potent lipid-lowering drugs. Thus, another therapeutic option is urgently needed. Our laboratory found that B1a B cells protect against atherosclerosis. We will study the therapeutic efficacy of expanding B1a cells by different approaches in atherosclerosis. Our proposal for clinical translation is to reduce mortality from atherosclerosis-based heart attacks and strokes.
Defining The Cellular Basis For Therapeutic Angiogenesis: Characterisation Of Endothelial Progenitor Cell Populations
Funder
National Health and Medical Research Council
Funding Amount
$365,126.00
Summary
Endothelial progenitor cells (EPCs) have been thought to play a role in new blood vessel growth and repair of the heart & blood vessels. Owing to their potential regenerative capacity, there has been immense interest in EPCs as a means of facilitating new blood vessel growth for sufferers of cardiovascular disease. This study will comprehensively evaluate the role of EPCs in new blood vessel formation. It will have implications for potential use of EPCs to treat heart disease.