E-CADHERIN AS A KEY MOLECULE IN RENAL EPITHELIAL-MESENCHYMAL TRANSITION AND FIBROSIS
Funder
National Health and Medical Research Council
Funding Amount
$318,267.00
Summary
Chronic kidney disease (CKD) is a major cause of death and disability in the Australian population. Current treatments for CKD are non-specific and frequently ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year more than 1700 Australians require kidney replacement therapy for this reason and many more die of kidney failure or its complications. Kidney fibrosis is the final common result of diverse CK ....Chronic kidney disease (CKD) is a major cause of death and disability in the Australian population. Current treatments for CKD are non-specific and frequently ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year more than 1700 Australians require kidney replacement therapy for this reason and many more die of kidney failure or its complications. Kidney fibrosis is the final common result of diverse CKD. This project proposes to investigate EMT, a key event in the development of renal fibrosis, whereby kidney cells are converted to fibrogenic cells. The project focuses on matrix enzymes (metalloproteinases) and E-cadherin (a molecule which is involved in adherence of kidney cells to one another, but which we think may actually be involved in the causation of EMT). This focus is novel, and could provide new understanding about the process of EMT in renal fibrosis, knowledge relevant to all diseases characterised by eventual loss of organ function due to fibrosis. It will identify new targets for therapy aimed at preventing fibrotic diseases of all types.Read moreRead less
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