Control Of Catecholamine Synthesis And Secretion By Angiotensin II.
Funder
National Health and Medical Research Council
Funding Amount
$271,650.00
Summary
In the stress response the catecholamines, including adrenaline, are secreted by the adrenal gland and the brain. This leads to the synthesis of new catecholamines in order to replace those that were lost. Synthesis of catecholamines is controlled by the activity and the amount of the enzyme tyrosine hydroxylase. Catecholamine synthesis and secretion is therefore a fundamental physiological process. This can be controlled by a number of mechanisms, including hormones such as angiotensin II. Angi ....In the stress response the catecholamines, including adrenaline, are secreted by the adrenal gland and the brain. This leads to the synthesis of new catecholamines in order to replace those that were lost. Synthesis of catecholamines is controlled by the activity and the amount of the enzyme tyrosine hydroxylase. Catecholamine synthesis and secretion is therefore a fundamental physiological process. This can be controlled by a number of mechanisms, including hormones such as angiotensin II. Angiotensin II has a number of functions including the control of blood pressure and body fluid homeostasis. Angiotensin II acts on the adrenal glands, the sympathetic nerves and the brain to produce these effects. It does so by increasing the secretion of catecholamines and these in turn modulate blood pressure and fluid homeostasis. The mechanism(s) whereby angiotensin II induces catecholamine secretion is not known, nor is it known how this leads to increased tyrosine hydroxylase activity and synthesis. The aim of this grant is therefore to determine how angiotensin II induces the activation of tyrosine hydroxylase, the secretion of catecholamines and the synthesis of new tyrosine hydroxylase. The significance of this work is that it will allow us to better understand how angiotensin II works and it will provide insights into the generation and control of hypertension and the mechanisms of the stress response. It is known that the pathways involved in angiotensin II stimulation of catecholamine secretion can be blocked by inhibitors of protein kinases and this leads to a reduction in blood pressure. It is therefore likely that this work will have therapeutic implications.Read moreRead less
Deciphering How PTEN Phosphatase Mediates Excitotoxic Neuronal Death
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
In stroke patients, oxygen deprivation indirectly induces massive nerve cell death by activating a cell death-promoting enzyme called PTEN. We aim at unravelling (i) how PTEN is activated by oxygen deprivation, (ii) where the activated PTEN is localised in cells, and (iii) how the activated and optimally localised PTEN induces nerve cell death. The study will benefit development of therapeutic strategies to protect against brain damage in stroke.
How Does The P75 Neurotrophin Receptor Transmit Both Pro-survival And Pro-apoptotic Signals In Neurons?
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
Signaling by the two NGF receptors, TrkA and p75, determines the survival or death of sensory neurons and of certain brain neurons involved in memory and learning. The most baffling aspect of these receptors is that in most circumstances they cooperate with each other to maximise the survival of neurons when NGF is present, but in some situations they are opposed to each other. In the latter case, NGF treatment can lead to death, rather than rescue, of neurons. In the last three years we have de ....Signaling by the two NGF receptors, TrkA and p75, determines the survival or death of sensory neurons and of certain brain neurons involved in memory and learning. The most baffling aspect of these receptors is that in most circumstances they cooperate with each other to maximise the survival of neurons when NGF is present, but in some situations they are opposed to each other. In the latter case, NGF treatment can lead to death, rather than rescue, of neurons. In the last three years we have developed novel antisense oligonucleotides which can be used to switch off each receptor separately. These have been, and will continue to be, particularly valuable tools for our research. We have also uncovered a novel way in which the two receptors interact (via a signal transduction molecule known as SHC), which provides us with a competitive edge in this area. We have the expertise and equipment to identify and clone the missing factors that account for the paradoxical interactions between p75 and TrkA. A successful outcome from this project will have important benefits by improving our understanding of the factors controlling neuronal fate, and will help to develop treatments for neurodegenerative diseases.Read moreRead less
The Role Of Ryk/AF6/Eph Complexes In Neuronal Pathfinding/fasciculation
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
Summary
During embryonic development nerve cells in the central nervous system have to find the right connections to make with other nerve cells. The process by which nerve cells find the right partners to make connections with is called neuronal pathfinding. Once some nerve cells have made the right connections, other nerve cells attach to these cells and form bundles of nerve fibres. This process is called fasciculation or bundling. This whole process is vital to the normal development and function of ....During embryonic development nerve cells in the central nervous system have to find the right connections to make with other nerve cells. The process by which nerve cells find the right partners to make connections with is called neuronal pathfinding. Once some nerve cells have made the right connections, other nerve cells attach to these cells and form bundles of nerve fibres. This process is called fasciculation or bundling. This whole process is vital to the normal development and function of the central nervous system and the brain. Without the right connections between nerves, information could not be received, processed or sent to organs in the body. We are now starting to discover some of the molecules which control the process of nerve cell pathfinding during development. It has been known for some time that proteins called Eph receptors play an important role in neuronal pathfinding and development of the head region in mice. We have now discovered that two other proteins called Ryk and AF-6 are able to bind to Eph receptors. We have very recently created mice which lack the Ryk protein and these mice have defects in their head deveopment strikingly similarto the head defects seen in mice that lack Eph receptors. We now wish to see whether Ryk mice have defects in neuronal pathfinding and fasciculation as do mice lacking Eph receptors. We also think that Ryk, Af-6 and Eph receptors form a protein complex which can modify cell function. We now wish to explore how this protein complex can do this.Read moreRead less