A Novel Mechanism For The Maintenance Of Catecholamine Synthesis
Funder
National Health and Medical Research Council
Funding Amount
$356,250.00
Summary
Stress causes an acute response that prepares us for flight or a fight and an adaptive response that requires days to establish. The catecholamines, including adrenaline, noradrenaline and dopamine are critical to both the acute and adaptive stress responses. They are secreted from cells at the level of the nervous system and the adrenal gland. We all respond differently to stress and if we do not cope we can become hypertensive or depressed. These pathologies require drug management and the dru ....Stress causes an acute response that prepares us for flight or a fight and an adaptive response that requires days to establish. The catecholamines, including adrenaline, noradrenaline and dopamine are critical to both the acute and adaptive stress responses. They are secreted from cells at the level of the nervous system and the adrenal gland. We all respond differently to stress and if we do not cope we can become hypertensive or depressed. These pathologies require drug management and the drugs all affect the catecholamine systems. Tyrosine hydroxylase controls catecholamine synthesis and it is activated in both the acute and adaptive phases of the stress response in order to replace catecholamines that have been secreted. Tyrosine hydroxylase is activated by protein phosphorylation in the acute phase and by the synthesis of new tyrosine hydroxylase in the adaptive phase. We have now discovered an additional and novel phase that we refer to as sustained tyrosine hydroxylase activation. This phase spans at least the period between the acute (mins) and adaptive phases (days). It involves the sustained phosphorylation of tyrosine hydroxylase and its mechanism appears to differ from the other two phases. In this project we will answer three questions. Does sustained tyrosine hydroxylase activation: 1 Occur in response to many stimuli and in many catecholamine cell types? 2 Occur by a single mechanism, different to the other phases, in all circumstances? 3 Play a role in the control of blood pressure and depression? This project will provide fundamental data about the mechanisms and consequences of sustained tyrosine hydroxylase activation, which is a part of the stress response not previously discovered. The data may impact on the way we design drugs to control stress responses, including antidepressants and antihypertensives.Read moreRead less
Interactions Between Developmental NMDA Receptor Dysfunction, Genetic Vulnerability And Early-life Stress In Schizophrenia: Studies Of Dysbindin Mutant Mice And Living Individuals At High Risk Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$347,457.00
Summary
This project will investigate two key pathways implicated in schizophrenia: glutamatergic (excitatory) neurotransmission and stress signalling. We will study how glutamatergic deficits emerge across postnatal development, in the presence or absence of early-life stress, in a schizophrenia-relevant mouse model, and investigate the interactions between stress and glutamatergic deficits in neuroepithelial cells from living individuals at high risk of schizophrenia.
Targeting Early Cellular Damage During Secondary Degeneration Using Nanosphere-based Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$424,407.00
Summary
After brain injury, there are no treatments to stop the spread of damage to intact tissue, a process involving different cell types and biochemical events. Clinical trials have targeted one event and have failed because large therapeutic doses are toxic and because combined treatments are needed to target different events. We will harness nanotechnology to target delivery of small, sustained doses of one or more drugs to specific cell types and biochemical events to stop the spread of damage.
Metabolism And Neurotoxicity Of Hemin And Hemin-derived Iron
Funder
National Health and Medical Research Council
Funding Amount
$346,400.00
Summary
Stroke is a leading cause of death and disability in industrialised countries. Much of the brain damage that follows a hemorrhagic stroke is attributable to the presence of free iron which mediates oxidative stress in brain cells. This iron originates from hemin, which in turn is derived from the hemoglobin in extravasated blood cells. The fact that iron is freed from hemin in the post-stroke period makes it an attractive therapeutic target. However, remarkably little is known about the metaboli ....Stroke is a leading cause of death and disability in industrialised countries. Much of the brain damage that follows a hemorrhagic stroke is attributable to the presence of free iron which mediates oxidative stress in brain cells. This iron originates from hemin, which in turn is derived from the hemoglobin in extravasated blood cells. The fact that iron is freed from hemin in the post-stroke period makes it an attractive therapeutic target. However, remarkably little is known about the metabolism of hemin by the different types of brain cells. The present project investigates the metabolism and neurotoxicity of hemin in brain cells and will examine the capacity of potential therapeutic agents to protect brain cells from hemin toxicity. The data obtained from this project will advance our understanding of the uptake and metabolism of hemin by the four main types of brain cell, and the factors that are likely to be involved in the neurotoxicity of hemin-derived iron following hemorrhagic stroke. The study will also provide data concerning the relative effectiveness of potential therapeutic agents, and information concerning the cell types, time points and aspects of hemin metabolism that are most effectively targeted by these agents. Such advances will guide the development of therapeutic approaches that are directed at minimising the brain damage which results from hemin-derived iron in humans.Read moreRead less