Targeting NPY Mechanisms In Rodent Models Of Generalised Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$437,637.00
Summary
This project will provide important information regarding the pharmacological mechanisms by which NPY acts to suppress seizures in animal models of epilepsy. It will provide strategies regarding potential new treatments of absence epilepsy.
NPY Suppresses Seizures And Modulates Thalamocortical Activity In Animal Models Of Generalized Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$386,020.00
Summary
Epilepsy is the most common serious chronic neurological disease in the community, affecting up to 3% of the population in a lifetime and 0.5-1% at any one time. Absence epilepsy is one of the most common types of epilepsy, most frequently seen in childhood and teenage years that may persist into adulthood. Anti-epileptic drugs are effective in controlling absence seizures in most patients, however there is an important group (20-40%) of patients in whom the absence seizures remain uncontrolled ....Epilepsy is the most common serious chronic neurological disease in the community, affecting up to 3% of the population in a lifetime and 0.5-1% at any one time. Absence epilepsy is one of the most common types of epilepsy, most frequently seen in childhood and teenage years that may persist into adulthood. Anti-epileptic drugs are effective in controlling absence seizures in most patients, however there is an important group (20-40%) of patients in whom the absence seizures remain uncontrolled with current medications. Recently there has been considerable interest in the role that chemical in the brain, such as neuropeptide Y (NPY), may play in epilepsy. The research proposed will examine the role of NPY in several animal models of absence epilepsy. We have recently shown that NPY suppresses absence seizures in a rat genetic model of generalised epilepsy, and that this appears to be mediated by Y2 receptors. This work will build on these novel findings, and determine the localisation of the effect within the brain, and the underlying mechanism. We will check NPY effects across several models in different species, a genetic rat model with spontaneous seizures, and in mice treated with a chemical to induce seizures. This will determine its broad applicability. We will also determine the effects of removal of NPY or NPY receptors on the effects of NPY on seizure expression. Finally, brain recording techniques will be applied to determine the mechanism and site within the brain underlying the protective actions of NPY. The project has the potential to provide novel insights into the role of NPY in the expression and modulation of absence seizures. NPY related mechanisms might represent targets for the development of a new class of therapeutic agents for the treatment of absence epilepsy. Targets that are identified as being important in the expression of absence seizures may also prove to be relevant in other types of generalised epilepsy syndromes.Read moreRead less
Interactions Between RAGE And The Type 1 Angiotensin Receptor Determine The Pro-atherosclerotic Actions Of Angiotensin II
Funder
National Health and Medical Research Council
Funding Amount
$521,956.00
Summary
Heart attacks and strokes are a major cause of death and disability in Australians. Activation of the renin angiotensin system plays a key role in the development and progression of atherosclerosis, the process that leads to narrowing and obstruction of arteries. In preliminary data we have found a way to block these pathways without affecting the control of blood pressure. We believe that interventions based on these data will be important for the prevention and treatment of heart disease.
The team has been at the forefront of research on type 1 diabetes for over a decade. This form of diabetes is a major chronic disease from childhood, as well as accounting for at least 10% of adult-onset diabetes. It occurs when the body�s immune system attacks and destroys the beta cells in the pancreas that make insulin, the hormone that controls the level of glucose in the blood. The team was one of the first in the world, and is the only one in Australia, to develop screening programs to tes ....The team has been at the forefront of research on type 1 diabetes for over a decade. This form of diabetes is a major chronic disease from childhood, as well as accounting for at least 10% of adult-onset diabetes. It occurs when the body�s immune system attacks and destroys the beta cells in the pancreas that make insulin, the hormone that controls the level of glucose in the blood. The team was one of the first in the world, and is the only one in Australia, to develop screening programs to test and identify people at risk for type 1 diabetes. They showed that the underlying disease could start years before symptoms occurred and discovered genes that determine the rate at which the underlying disease progresses. They have also found evidence that the disease may be triggered by gut viruses called rotaviruses in genetically-susceptible individuals. They showed that type 1 diabetes could be prevented in a mouse model by getting the immune system to make a protective response to insulin, and then went on to apply this in at-risk humans in a controlled trial of intranasal insulin, the first of its kind. They have used genetic techniques not only to pinpoint the mechanisms responsible for killing the beta cells but also to modify the beta cells to make them resistant to attack by these mechanisms. The multidisciplinary approach of the team will be directed to further understanding the genetic and environmental factors underlying type 1 diabetes and the immune mechanisms, particularly involving special white blood cells called T cells, that kill beta cells. A molecular target of the immune attack, the parent of insulin called proinsulin, will be used, paradoxically, as a tool to regulate the immune system and avert the attack. This will be achieved by giving proinsulin via the mucosa of the naso-respiratory tract or via the bone marrow-derived stem cells, initiallyin the mouse model as a test of feasibility for human application. In parallel with these approaches to prevention, specially constructed viruses will be used to transfer several new genes into beta cells to improve their resistance to immune attack, so that they can be transplanted into people with established diabetes without the need for potentially toxic drugs that suppress the immune system overall. The integrated research of the team is helping to provide a sound, rational base for the eventual prevention and cure of type 1 diabetes.Read moreRead less
Spatial And Temporal Dimensions Of Mu-opioid Receptor Signalling: Implications For The Development Of Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$799,316.00
Summary
The use of morphine as an analgesic is still limited by undesirable side effects such as tolerance. Despite decades of research, the mechanisms behind the development of tolerance are poorly understood. The ? opioid receptor is a protein expressed at the surface of the cells that is the target of morphine. This project will investigate the signalling events triggered by opioids with unprecedented resolution and will aim to elucidate why morphine elicits more tolerance than other opioid drugs.
Type 1 diabetes (T1D) is a major chronic disease affecting over 100,000 Australians. Its treatment and complications impose a significant burden on affected individuals and their families and on the health system. T1D occurs when the immune system attacks insulin-producing cells in the islet cells of the pancreas. The team has developed ways to identify at-risk people, defined immune and genetic causes of T1D and is undertaking prevention trials and Australia's first islet transplant program. Th ....Type 1 diabetes (T1D) is a major chronic disease affecting over 100,000 Australians. Its treatment and complications impose a significant burden on affected individuals and their families and on the health system. T1D occurs when the immune system attacks insulin-producing cells in the islet cells of the pancreas. The team has developed ways to identify at-risk people, defined immune and genetic causes of T1D and is undertaking prevention trials and Australia's first islet transplant program. Their multidisciplinary research is taking us closer to the prevention and cure of T1D.Read moreRead less
Derivation Of Pancreatic Beta Cells From Embryonic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$2,968,050.00
Summary
People with type 1 diabetes require regular insulin injections because the organ that normally makes insulin, the pancreas, no longer functions. The goal of this program is to derive human fetal pancreas tissues from embryonic stem cells. Such tissue could be used to replace the missing insulin producing cells in people with type 1 diabetes. The program brings together expertise in ES cell biology at Monash University and the leading diabetes research at the Walter and Eliza Hall Institute.
Functional Suicide Of Selected Dendritic Cells By Cytochrome C: An In Vivo Model Lacking Cross-presentation
Funder
National Health and Medical Research Council
Funding Amount
$597,476.00
Summary
Certain white blood cells (dendritic cells) activate the immune system, especially its T cells. Infection of such cells elicits killer T cell responses. However not all infections infect dendritic cells. In such cases, the infectious material is eaten by dendritic cells and moved to certain areas within the cell. This process is called cross-presentation and how important it is during various diseases remains moot. We now have a model of testing this by eliminating these cross-presenting cells.