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
Characterisation Of A Type V Secretion In Escherichia Coli And Determining Its Role In Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$73,195.00
Summary
Disease causing bacteria assemble secretion systems to assist with colonisation, persistence and destruction of host tissue. These systems have been categorised as Type I to Type VI. A comprehensive understanding of these secretion systems, is of paramount importance for a complete understanding of bacterial pathogenesis. We will investigate the role of a novel Type V secretion system conserved amongst many human pathogens.
Molecular Determinants Of Amino Acid-dependent Signalling By The Calcium-sensing Receptor
Funder
National Health and Medical Research Council
Funding Amount
$566,035.00
Summary
Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat. Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for tightly regulating cellular responses depending upon their levels in b ....Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat. Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for tightly regulating cellular responses depending upon their levels in blood. Identifying amino acid sensing molecules and identifying the mechanisms they use to control cellular responses is thus a key issue in human biology. The applicant identified the calcium-sensing receptor as an amino acid sensor and has shown that this receptor provides a means by which fluctuations in amino acid levels regulate the secretion of the key calcium-regulating hormone, PTH. In the current proposal, the mechanisms that link amino acid activation of the calcium-sensing receptor to its key cellular responses will be determined.Read moreRead less
The Role Of Vitamin D In Beta-cell Function And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$554,248.00
Summary
Vitamin D deficiency is common in Australia, with the success of the 'slip, slop, slap' campaigns. Low levels of Vitamin D have been associated with diabetes. This grant aims to determine how vitamin D affects insulin release and blood glucose levels.