Suppression Of NADPH Oxidase-derived Oxidative Stress By Anti-sense Probes And HDL In Human Vascular Endothelium
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) develo ....In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) developed in our laboratory, which block a particular gene causing oxidative stress, we will determine whether this gene is responsible for the formation of oxyradicals in human and mouse cells grown in culture. In addition, we will explore whether this gene is turned on by factors known to be involved in CHD. Finally, we will also investigate whether the good cholesterol known as HDL can act to prevent oxidative stress in human cells, as we discovered it appears to do in living arteries in vivo. If we find it has the same protective effect in endothelium, we will determine how it does this, and which component proteins of the HDL particle are important. This might suggest new treatments to prevent acute events leading to heart attack and stroke, and possibly new applications where damage appears to result from acute oxidative stress, such as in the brain soon after a stroke has occurred. We also have a plan to develop antisense drugs that will target the important gene specifically in the affected endothelium. In addition, we have other specific new drugs that will block this system in arteries. Simultaneously we will be testing the role of this gene in mouse and rabbit models of artery disease, for both our types of drugs might provide valuable new therapeutic agents to target the underlying cause of CHD and not just its symptoms as current drugs do.Read moreRead less
Endothelial Development From Pluripotent Stem Cells As A Means To Study Pathology In Pulmonary Artery Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$613,311.00
Summary
Pulmonary artery hypertension (PAH) is a fatal disease primarily affecting young adults. It is caused by a defect in cells that form the vessel that carries blood from the heart to the lungs. We will use stem cells made from the skin of PAH patients to examine why the blood vessel cells from these patients fail to function normally.
Local Sleep In The Awake Brain: An Underlying Cause Of Neurobehavioural Deficits In Sleep Apnea?
Funder
National Health and Medical Research Council
Funding Amount
$582,330.00
Summary
Obstructive sleep apnea (OSA) is a common sleep disorder which significantly impacts daytime functioning leading to excessive sleepiness, and problems with attention and thinking. Currently, the causes for cognitive impairment in OSA (including attentional lapses and performance deficits) are poorly understood. In the awake state, groups of neurons can briefly go “offline” as they do in sleep. These periods of “local sleep” may explain impaired task performance in OSA.
Transdermal Testosterone Therapy: A Potential Treatment For Selective Serotonin Reuptake Inhibitor (SSRI)-associated Sexual Dysfunction In Women
Funder
National Health and Medical Research Council
Funding Amount
$241,351.00
Summary
Female sexual dysfunction (FSD) is frequently reported with selective serotonin reuptake inhibitor (SSRI) therapy and venlafaxine, these being the most common antidepressants used by Australian women. We have shown that testosterone therapy significantly improves sexual function in women with FSD. However SSRI-users have been excluded from these past studies. The aim of this study is to assess the efficacy of transdermal testosterone therapy for treatment of sexual dysfunction associated with SS ....Female sexual dysfunction (FSD) is frequently reported with selective serotonin reuptake inhibitor (SSRI) therapy and venlafaxine, these being the most common antidepressants used by Australian women. We have shown that testosterone therapy significantly improves sexual function in women with FSD. However SSRI-users have been excluded from these past studies. The aim of this study is to assess the efficacy of transdermal testosterone therapy for treatment of sexual dysfunction associated with SSRI therapy.Read moreRead less
Imaging Neutrophil And Endothelial Function In Acute Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$545,517.00
Summary
The glomerulus is a group of small blood vessels which form the filtering component of the kidney. In many diseases, it can be the target of an inappropriate inflammatory response during which white blood cells accumulate in the glomerular blood vessels and cause damage. In this project, we will visualise the blood vessel lining of the glomerulus in order to understand how white blood cells damage this region and cause leakage of protein leak into the urine.
S100A8/A9 As A Target In Metabolic Diseases To Inhibit The Acceleration Of Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$554,990.00
Summary
Obesity and diabetes are the leading cause of premature death, due to accelerated cardiovascular disease (CVD). The abundance of blood monocytes influences the progression and regression of CVD. We discovered that S100A8/A9 promotes monocyte production in obesity and diabetes. This project will explore how S100A8/A9 is produced in diabetes and obesity and if blocking its function using a novel drug will prevent obesity and diabetes associated CVD.
Transplantation of pancreatic islets is the only cure for type 1 diabetes (T1D). Unfortunately, many of the transplanted islet cells die quickly due to an inadequate supply of blood. Herein, we investigate a novel cell surface protein for its role in islet and blood vessel survival and function. Furthermore, we use nanotechnology to provide said protein to the islet cells during transplantation for increased survival and function. Ultimately, this work may cure more patients with diabetes.
Exploring The Therapeutic Potential Of TRAIL In Diabetes And The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$446,374.00
Summary
TNF-related apoptosis-inducing ligand (TRAIL) is a protein with potentially useful actions in human health and disease. TRAIL is able to prevent atherosclerosis, the cause of heart attacks and strokes. In addition, we have recently shown that its actions on fat and the pancreas may prevent the development of the metabolic syndrome and type 2 diabetes. These studies will explore the therapeutic potential of TRAIL for the prevention of diabetes and heart disease in a range of animal models.
The Role Of Dicarbonyl-derived AGEs And RAGE In Diabetes Associated Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$470,617.00
Summary
Based on our pilot data we postulate that glucose derived molecules such as methylglyoxal (MGO) have effects on inflammation and oxidative stress leading to accelerated atherosclerosis in diabetes. Our studies aim to identify novel treatments which block these effects thus leading to superior protection and prevention of atherosclerosis in diabetes.
The Persisting Vascular Effects Of Activation Of The Renin-Angiotensin System
Funder
National Health and Medical Research Council
Funding Amount
$628,456.00
Summary
Heart attacks and strokes are the major cause of death and disability in Australians. Heart disease is widely viewed to be the legacy of our diet and lifestyle, and even that of our parents. We propose to explore in detail the molecular mechanism of how this imprinting comes about and identify new targets to prevent, retard or reverse heart disease.