I am a cellular physiologist investigating the role of ion channels, receptors and intracellular signalling systems in the control of hormone secretion from endocrine cells, contraction of cardiac myocytes and to a lesser extent, growth of endometrium can
The Role Of The Gastric H/K ATPase In Parietal Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$166,885.00
Summary
The cells of the body contain many specialised membrane structures. At present it is not clear how the synthesis of these stuctures is directed. To study this problem we are examining the acid secretory parietal cells of the stomach. These cells have a very elaborate membrane system that contains a major proton pump protein. By manipulating the levels and form of the proton pump we will gain novel insights into the mechanism of membrane structure and function.
Novel Mechanisms In Regulating Cytokine Secretion In The Inflammatory Response
Funder
National Health and Medical Research Council
Funding Amount
$323,160.00
Summary
Macrophages are key cells in the immune and inflammatory response. They play a role in many biological processes including wound healing and resistance to tumours and infections. It is also a major cell involved in mediating inflammation and tissue damage in chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis. The macrophage's role in these processes is achieved in large part by secreting enzymes and other proteins called cytokines to the outside of the cell. These cyt ....Macrophages are key cells in the immune and inflammatory response. They play a role in many biological processes including wound healing and resistance to tumours and infections. It is also a major cell involved in mediating inflammation and tissue damage in chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis. The macrophage's role in these processes is achieved in large part by secreting enzymes and other proteins called cytokines to the outside of the cell. These cytokines are synthesized by the macrophage and travel through a secretory pathway in the cell, in order to be released to the outside of the cell. There are various quality control mechanisms along the pathway which ensure only correctly made functional protein is secreted out of the cell. One cytokine, called macrophage inhibitory cytokine is produced by the immune cells called macrophages only when they become activated to mount an immune response against invading pathogens. The cell uses a novel mechanism to ensure the quality control of this cytokine. The propeptide of this cytokine targets incorrectly folded cytokine to a protein complex called the proteasome for degradation. This prevents secretion of inactive cytokine. Additionally, the propeptide of the cytokine helps secretion from macrophages by a novel mechanism. Because of these characteristics the cytokine provides a good model to study secretion from macrophages under pro- and anti-inflammatory conditions. In addition, demonstrating that activation of the macrophages causes a major upregulation in the synthesis and secretion of cytokines by novel mechanisms, will further our understanding of how the macrophage operates in fulfilling its role in the immune response.Read moreRead less
P2X7 Receptor And Inflammation In The Pathophysiology Of Mood Disorders
Funder
National Health and Medical Research Council
Funding Amount
$598,063.00
Summary
Mood disorders are chronic disabling mental illnesses affecting a significant proportion of the population. Inherited variations in a particular gene involved in inflammation will be investigated in individuals with mood disorders. This work aims to understand the relationship between inflammation of parts of the brain and mood disorders leading to the potential development of a new therapeutic target.
Theoretical And Computational Studies On Voltage-Gated Potassium (Kv) Channels
Funder
National Health and Medical Research Council
Funding Amount
$427,796.00
Summary
The primary aim of the proposed projects is to understand how biological ion channels work. All electrical activities in the nervous system, including communication between cells and influences of hormones and drugs on cell function, are regulated by the opening and closing of ion channels. We will study, applying rigorous physical principles and engineering methods and using powerful supercomputers, a class of biological ion channels, known as the voltage-activated potassium channels.
Secretion is an essential step in memory and learning, control of metabolism and reproduction and the functioning of most organs. Secretory dysfunction also underlies many diseases including type 2 diabetes. We plan experiments to test for a new model of control of insulin secretion.
Do Synaptic-like Mechanisms Control Insulin Secretion?
Funder
National Health and Medical Research Council
Funding Amount
$593,235.00
Summary
An estimated 415 million people world-wide were diagnosed with diabetes in 2015. One of the causal factors in disease is the dysregulation of insulin secretion. We have developed new techniques to study insulin secretion that has led us to propose a new model for secretory control. This proposal sets out experiments to critically test this model. The outcomes could have wide-reaching impact on understanding and for future treatment and prevention of the diabetes.
Deciphering The Molecular Steps Leading To The Potentiation Of Neuronal Exocytosis By Arachidonic Acid
Funder
National Health and Medical Research Council
Funding Amount
$273,000.00
Summary
Release of hormones and neurotransmitters relies on a process called exocytosis which involves SNARE proteins: syntaxin1A and SNAP-25 on the target plasma membrane and VAMP on the vesicular membrane. Availability of the t-SNARE on the plasma membrane is believed to play a major role in controlling the amount of exocytosis. Syntaxin1A bound to Munc18 constitute an 'unproductive-reserve' pool of closed Syntaxin that cannot interact with SNAP-25. Intracellular messengers capable of releasing Syntax ....Release of hormones and neurotransmitters relies on a process called exocytosis which involves SNARE proteins: syntaxin1A and SNAP-25 on the target plasma membrane and VAMP on the vesicular membrane. Availability of the t-SNARE on the plasma membrane is believed to play a major role in controlling the amount of exocytosis. Syntaxin1A bound to Munc18 constitute an 'unproductive-reserve' pool of closed Syntaxin that cannot interact with SNAP-25. Intracellular messengers capable of releasing Syntaxin1A from Munc18 thereby making it available to interact with SNAP-25, are foreseen to play a major role in potentiating exocytosis - a process with ramification for memory and learning. We have identified arachidonic acid, a lipidic messenger which fullfil this role. For the first time we are in a position to manipulate at the molecular level different pools of SNARE proteins with direct implications for our understanding of the mechanism of secretion. Very few models are currently available to understand how learning and memory occur in the brain. Our research points to a new direction: the amount of 'active' and 'unproductive-reserve' pools of SNARE proteins present on the plasma membrane of neurosecretory cells are in dynamic equilibrium and arachidonic acid, a second messenger capable of trans-synaptic action, can modify this equilibrium resulting in an increase of the amount of 'active' SNARE thereby potentiating the amount of transmitter-hormone released by exocytosis. Importantly, this research lays the basis for a dynamic view of the secretory mechanism with important implications for treatment of diseases such as diabetes and neurodegenerative diseases. Our hope is that by understanding at the molecular level how secretory cells regulate the amount of their secretion, we will be in a position to modify these parameters in order to counteract illnesses of the nervous system.Read moreRead less