Relaxin-3 Systems In Brain: Validation Of Neural Targets And Functional Roles
Funder
National Health and Medical Research Council
Funding Amount
$537,579.00
Summary
Our laboratory recently discovered the brain 'transmitter' called 'relaxin-3', and are researching how it affects brain activity and animal physiology and behaviour. Findings suggest that relaxin-3 can modulate memory, responses to stress and other complex behaviours. Identifying the various actions of relaxin-3 in the brain could provide potential new treatments for conditions such as anxiety-depression, cognitive deficits (dementia) and schizophrenia.
Throughout our lives cells must die and be replenished. One way multicellular organisms remove unwanted cells is through a process called programmed cell death. This process eliminates redundant, damaged or infected cells by a program of cell suicide. We are studying the underlying molecular mechanisms of this cell suicide in order to design new pharmaceuticals to treat illnesses caused by a disruption in programmed cell death. The fine balance between living and dying cells must be maintained a ....Throughout our lives cells must die and be replenished. One way multicellular organisms remove unwanted cells is through a process called programmed cell death. This process eliminates redundant, damaged or infected cells by a program of cell suicide. We are studying the underlying molecular mechanisms of this cell suicide in order to design new pharmaceuticals to treat illnesses caused by a disruption in programmed cell death. The fine balance between living and dying cells must be maintained and if this balance is lost then disease may result. A reduced level of cell death may result in cancers while too many dying can contribute to degenerative diseases such as Alzheimer's disease and stroke. Currently many of these diseases do not have effective treatments. We will determine the three-dimensional structures of key proteins involved in programmed cell death and use this information to design drugs that can interfere with the molecular processes involved in signalling cell death. Such drugs may prove useful new therapies in a wide range of diseases caused by a breakdown in the biochemical paths to cell death.Read moreRead less
Identification Of The Plasmodium Falciparum Translocon That Exports Parasite Proteins Into Their Erythocytic Hosts.
Funder
National Health and Medical Research Council
Funding Amount
$409,027.00
Summary
Up to 10% of the world's population will suffer from malaria in any given year and for over a million this disease will be fatal. This devastating disease is caused by the parasite Plasmodium falciparum that infects and destroys our red blood cells. Infected red cells are greatly modified by the parasites so they can feed and avoid elimination by the human immune system. We wish to investigate the red blood cell modification process and assess it as a potential target for anti-malarial drugs.
In cancer cells the normal process of cell death (called apoptosis) is defective, helping abnormal cells to grow and multiply unchecked. The Bak protein is a member of the Bcl-2 family of apoptosis regulators, and plays a pivotal role in mediating cell death. By defining each step in Bak-mediated apoptosis, we aim to better understand how cancer cells accumulate, and how targeting the Bcl-2 family may lead to effective anti-cancer therapeutics.
Role Of Bak And Bax Membrane Anchors In Targeting And Apoptotic Pore Formation.
Funder
National Health and Medical Research Council
Funding Amount
$352,319.00
Summary
In cancer cells the normal process of cell death (called apoptosis) is defective, helping abnormal cells to grow and multiply unchecked. The Bak and Bax proteins are members of the Bcl-2 family of apoptosis regulators, and play a pivotal role in mediating cell death. By defining how these proteins form a pore in mitochondria, the point of no return in cell death, will help the development of novel anti-cancer agents that target the Bcl-2 family in general, and Bak and Bax in particular.
Role Of Immediate Early Gene Induction And AP-1 Activation In HDAC Inhibitor Induced Apoptosis.
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Histone deacetylase inhibitors (HDACi) are a novel class of anti-tumor agents, recently approved for the treatment of cutaneous T-cell lymphoma. The goal of this study is to improve our understanding of how this class of drug induces tumor cell death. These studies are designed to provide insight into which patients are most likely to benefit from treatment with these agents. Second, they will provide direction into how the therapeutic efficacy of HDACi may be enhanced, through combination with ....Histone deacetylase inhibitors (HDACi) are a novel class of anti-tumor agents, recently approved for the treatment of cutaneous T-cell lymphoma. The goal of this study is to improve our understanding of how this class of drug induces tumor cell death. These studies are designed to provide insight into which patients are most likely to benefit from treatment with these agents. Second, they will provide direction into how the therapeutic efficacy of HDACi may be enhanced, through combination with other existing therapeutics.Read moreRead less
Does Early Overnutrition Differentially Alter Hypothalamic Neuropeptides That Regulate Food Intake In The Rat
Funder
National Health and Medical Research Council
Funding Amount
$346,250.00
Summary
In Australia the incidence of obesity, in particular childhood obesity, is increasing dramatically, and the possible long term consequences of this are of great concern. The brain regulates appetite through a number of chemical transmitters such as neuropeptide Y (NPY) which is present in the brains of mammals and causes increased food intake. The effects of overeating from a young age on these brain transmitters has been largely ignored although this may impact on subsequent eating behaviour. I ....In Australia the incidence of obesity, in particular childhood obesity, is increasing dramatically, and the possible long term consequences of this are of great concern. The brain regulates appetite through a number of chemical transmitters such as neuropeptide Y (NPY) which is present in the brains of mammals and causes increased food intake. The effects of overeating from a young age on these brain transmitters has been largely ignored although this may impact on subsequent eating behaviour. In addition to NPY we will study other transmitters in the brain that have profound effects on appetite, some increasing, and others decreasing, food intake. These may form useful therapeutic targets for new drugs for obesity. Key targets we will study include melanocortins, glucagon-like peptide 1, urocortin, melanin concentrating hormone, agouti related peptide, and NPY. We will determine whether overnutrition from birth to weaning leads to changes in these appetite regulating neurotransmitters in the brain, and monitor the hormonal signals that impact on their activity. We will also determine whether early overnutrition exacerbates the subsequent responses to a high fat diet by comparison with rats made obese as adults. We will measure brain concentrations of the neurotransmitters, the amount released from the brain, and determine whether the feeding responses to injections of these agents is altered in obese animals. We have evidence that these transmitters interact in a co-ordinated fashion to affect feeding; this project will examine whether these interactions are maintained in the various types of obesity. Rats are commonly used for this type of study as the processes regulating feeding are very similar to those in humans and these agents cause similar effects in rats and humans. It is hoped that this information will provide new insight into the way brain adapts to overnutrition, and provide potential treatments for obesity and other feeding disorders.Read moreRead less
Enhancing The Cardioprotective Effect Of Diadenosine Tetraphosphate: Designing Inhibitors Against Ap4A Hydrolase
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitocho ....Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitochondrial ATP-dependent potassium channel may be in common with most pathways. Pretreatment with the compound diadenosine tetraphosphate (Ap4A) mimics ischemic preconditioning with noticeable reductions in tissue necrosis (cell death). This treatment has been shown in experimental work to protect the heart during periods of stress such as in heart surgery or recovery from an ischemic event. The biological site of action by Ap4A may be the mitochondria ATP-dependent potassium channel or an associated protein. Ap4A can be degraded by enzymes located inside and on the outside of heart cells, notably by two forms of Ap4A hydrolase. We will use antibody assays to understand the specific localization and amount of Ap4A hydrolase before and after ischemia and after ischemic preconditioning in human heart muscle and blood vessels. We propose to determine the structure of the enzyme and use novel computer methods to screen databases for potential inhibitors. These inhibitors of Ap4A hydrolase activity could aid the design of a potent inhibitor that would prevent Ap4A hydrolase from degrading Ap4A and therefore enhance the cardioprotective properties of Ap4A as well as minimizing side effects from the break down of Ap4A. We will also use these inhibitors and other known non-degradable Ap4A analogues in bioassays to test the relative significance of Ap4A hydrolase present in different cellular locations.Read moreRead less
Novel Therpeutic Approaches For Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$604,734.00
Summary
There are currently no effective treatments for Alzheimer's disease. In this application we will develop a novel class of compound to assess their potential as AD therapeutics. These compounds will be tested in vitro and in vivo models of Alzheimer's disease. The successful conclusion of the work described here would provide new leads suitable for further development as therapeutics for Alzheimer's disease.