Cardiac Arrhythmias And Cardiac Contractility During Stress: Regulation By Brainstem Medullary Raph Neurons
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
Life is stressful, and in subjects with predisposed hearts stressful events may provoke sudden life-threatening or fatal disturbances of the heart rhythm (arrhythmias). Activity in nerves that control the heart is the main trigger of arrhythmias. This activity is initiated in the brain, when, for example, we have a sudden emotional shock. At present, the neurochemistry and connections of the brain neurons responsible for arrhythmias, have not been identified. Our project is designed to find answ ....Life is stressful, and in subjects with predisposed hearts stressful events may provoke sudden life-threatening or fatal disturbances of the heart rhythm (arrhythmias). Activity in nerves that control the heart is the main trigger of arrhythmias. This activity is initiated in the brain, when, for example, we have a sudden emotional shock. At present, the neurochemistry and connections of the brain neurons responsible for arrhythmias, have not been identified. Our project is designed to find answers to these questions. Our hypothesis is that the responsible neurons are located in the midline portion of the medulla oblongata (the lower part of the brain); that activation of these neurons will increase cardiac function in a manner that may provoke arrhythmias; and, conversely, that their inhibition will protect the heart during stressful events by suppressing potentially arrhythmogenic neural signals. We hypothesise that cardiac-controlling neurons possess receptors for serotonin (one of the brain neurotransmitters), and that the neurons can be inhibited by drugs that selectively activate a specific subtype of these receptors. Our results will increase our understanding of the causes of cardiac arrhythmias by elucidating the link between emotional-psychological events in the brain and stress-induced cardiac events. Our findings could contribute to the identification of new drugs that will protect the heart during stress.Read moreRead less
This proposal aims to examine central mechanisms important in stress related hypertension. My team will focus on the role of tissue plasminogen activator in mediating inhibitory effects of chronic stress on neural plasticity and examine inhibitory dysfunction in GABAergic and nitric oxide pathways that lead to increased sympathetic activity and elevated blood pressure. Importantly, we will investigate the potential of three interventions directed at each as therapies for hypertension.
Investigation Into The Intervention Of Arterial Thrombosis And Atherosclerosis Using Shear Sensitive Nanoparticle Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$462,601.00
Summary
In this project we aim to provide a targeted therapy that inhibits atherosclerosis, in-stent restenosis and thrombosis; pathologies characterized by high shear stress due to a reduction in the vessel lumen. We will apply microfluidic technology to characterize lipid nano-capsules that are tagged with antibodies against activated platelets or VCAM-1, loaded with anti-platelet or immune suppressive drugs and are prone to rupture specifically under high shear stress conditions.
Hypertension is the major driver of cardiovascular disease affecting over a billion people. The cause is increasingly lifestyle related (obesity and stress) and activation of the nervous system is a major contributor in all cases. My vision for the next 5 years is discover the key underlying mechanisms within the central nervous system and the kidney that are primarily responsible for increasing nervous activity and blood pressure.
Potential Novel Pharmacological Strategies To Prevent Atherosclerotic Plaque Rupture
Funder
National Health and Medical Research Council
Funding Amount
$1,584,568.00
Summary
Most heart attacks are the consequence of the acute rupture of plaques in arteries that supply our heart with oxygen and nutrients. Current standard tests cannot distinguish plaques that likely rupture from plaques that do not rupture. Similarly, little is known about the processes that determine whether a plaque is vulnerable to rupture or stable. The current project examines the involvement of two processes - either alone or in combination - in determining plaque stability/vulnerability.
Oxidative Processes In Vascular Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$851,980.00
Summary
The process that turns cut fruit brown when it is exposed to air is thought to cause disease of our blood vessels and heart as we age. Despite what we first thought, 'blocking' this oxidation process with antioxidant supplements does not lower heart disease. This is because oxidation not only causes harm but also is useful and essential for normal body function. Our research program aims to show which oxidative processes are needed for blood vessel health or cause vessel disease.
Importance Of The Brain Renin-Angiotensin System For Regulating Blood Pressure And Cardiovascular Autonomic Function.
Funder
National Health and Medical Research Council
Funding Amount
$609,424.00
Summary
The peptide angiotensin a major regulator of many brain areas controlling blood volume and blood pressure. Brain angiotensin may well contribute to high blood pressure but how it acts in each of the different brain areas is unknown. New gene transfer technology using viruses combined with genetically modified mice will enable this project to inactivate or activate angiotensin in each brain nucleus and determine the role of individual areas to setting of blood pressure leading to hypertension.
NOX Isoforms In Diabetes Associated Vascular Injury: Implications For Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$441,511.00
Summary
These studies will investigate the role of oxidative stress and enzymes involved in oxidative stress production in diabetes associated blood vessel injury and kidney damage, leading to heart attacks, stroke and kidney failure. We will use unique knockout animal models and novel drug treatments. Ultimately, we aim to develop novel treatments to better treat and prevent diabetes related complications.
Fibrosis is a common feature of many forms of heart disease. Despite the recognised central role of reactive oxygen species (ROS) in cardiac fibrosis, antioxidant approaches have failed in clinical trials. We have discovered a new mechanism for ROS-mediated fibrosis that is depleted in human heart failure, and will test an innovative therapeutic approach that is imminently translatable given the development by members of our team of a specific peptide blocker effective in blocking this pathway.