NADPH Oxidase And Brain Repair After Ischaemic Stroke
Funder
National Health and Medical Research Council
Funding Amount
$641,877.00
Summary
Stroke is the third most common cause of death, results in considerable suffering and presents an enormous cost to health budgets. New research suggests that the injured brain can be stimulated to improve function. Generation of free radicals in the brain in the weeks after stroke may be important in long term recovery by promoting new blood vessel formation to suport brain repair. In this project we seek to identify how, when and where new blood vessels assist stem cell mediated repair.
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
Regulation Of Vascular Tone By Indoleamine 2,3-dioxygenase
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other condit ....As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other conditions, including certain diseases, so that it is not surprising that many of the commonly used cardiovascular drugs target to change blood vessel tone, either increasing or decreasing blood pressure, depending on the circumstances involved. The present application is based on the discovery, in the mouse, that during a systemic infection a specific protein is induced in the cells that line blood vessels. This protein degrades a certain amino acid into a novel chemical, called kynurenine. We observed that kynurenine has previously unrecognised vessel-relaxing properties. The present project will investigate the importance of kynurenine formation as a novel pathway in the regulation of vascular tone. Mice, in which the activity of the kynurenine-producing protein will be modulated (both up and down) will be used in conjunction with blood pressure and other relevant measurements. In addition, the role of a unique molecule, called superoxide anion radical, in the production of kynurenine by the protein will also be tested. If our results confirm that the protein and kynurenine are indeed involved in regulating vascular tone, our research could have tremendous impact on many aspects of normal physiology as well as cardiovascular diseases that remain the major single cause of death in Australia.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
The Critical Roles Of Heme Oxygenase-1 In The Response To Ischemia
Funder
National Health and Medical Research Council
Funding Amount
$690,593.00
Summary
Heme oxygenase-1 is a protein that recycles our body's iron which itself is essential for life because it is needed for the sensing, transport and use of oxygen we breath. The current project investigates a novel interplay between heme oxygenase-1 and our body’s major response to tissue oxygen becoming limited. By doing so, our project may provide the basis for novel treatments of conditions where arteries are obstructed, such as those that lead to heart attack and amputation.
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.
Hematopoietic Cytokines For The Repair Of Myocardial Infarction
Funder
National Health and Medical Research Council
Funding Amount
$334,375.00
Summary
Heart attacks remain one of the most common causes of heart failure. Unlike many other tissues such as the skin or bone marrow, the heart is unable to repair itself following a heart attack. Recently it has been recognised that bone marrow cells can to a small degree repair the heart. How this is done is not known but it may be due to the formation of new blood vessels and perhaps new heart muscle. Unfortunately, the repair by bone marrow cells is not very efficient. One way of improving the eff ....Heart attacks remain one of the most common causes of heart failure. Unlike many other tissues such as the skin or bone marrow, the heart is unable to repair itself following a heart attack. Recently it has been recognised that bone marrow cells can to a small degree repair the heart. How this is done is not known but it may be due to the formation of new blood vessels and perhaps new heart muscle. Unfortunately, the repair by bone marrow cells is not very efficient. One way of improving the efficiency of heart repair by bone marrow cells is to give people bone marrow growth factors that increase the number of bone marrow cells in the blood and thus, increase the number at the site of heart injury. Our preliminary research shows that this is the case although the efficiency of repair is still not enough as a useful therapy. This project will examine how bone marrow growth factors improve heart repair following heart attacks and explore ways of improving the efficiency of repair to permit trials in humans.Read moreRead less
Reversing Oxidative Inhibition Of The Na-K Pump By Beta3 Adrenergic Agonists: Implications For Heart Failure Therapy
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
Heart failure is a debilitating condition characterised by a decreased heart pump function. Raised Na+ levels and increased oxidative stress in cardiac cells are important in its causation. While traditional antioxidants are not useful in treatment, we have found that a group of drugs designed to induce weight loss can reverse oxidative inhibition of the mechanism that pumps Na+ out of heart cells. The effect of these drugs on the Na+ pumping mechanism and heart failure will be examined.