Targeting RCAN1 To Treat Type 2 Diabetes And Obesity
Funder
National Health and Medical Research Council
Funding Amount
$814,468.00
Summary
Obesity and impaired insulin secretion are significant contributors to Type 2 diabetes. In this project we demonstrate that a protein called RCAN1 contributes to both fat mass and insulin secretion and that this contribution is exacerbated in obesity and in Type 2 diabetes. We will identify how RCAN1 controls these major metabolic pathways with outcomes including the development of new therapeutics for obesity and Type 2 diabetes.
Brain Protection: A new therapeutic approach for Multiple Sclerosis In Multiple Sclerosis (MS), the immune system mistakenly attacks the brain. The immune attacks destroy myelin, the protective coat around electrical cables in the brain (demyelination). Current treatments for MS are only partially effective, and work by reducing the number and severity of these attacks. However, MS-related permanent disability in the majority of sufferers is due to the development of progressive MS, and current ....Brain Protection: A new therapeutic approach for Multiple Sclerosis In Multiple Sclerosis (MS), the immune system mistakenly attacks the brain. The immune attacks destroy myelin, the protective coat around electrical cables in the brain (demyelination). Current treatments for MS are only partially effective, and work by reducing the number and severity of these attacks. However, MS-related permanent disability in the majority of sufferers is due to the development of progressive MS, and current therapies do not reduce this progression. It is believed that one major cause of this permanent disability is permanent myelin loss. Interestingly, we have already shown that the growth factor LIF is made by the body during MS-like inflammation, and that it limits damage by directly protecting myelin-producing cells. However, the bodies own LIF production during inflammation is sub-maximal, because myelin protection can be enhanced by giving additional therapeutic LIF. This suggests that (1) The brain produces a defence response to harmful inflammation and that (2) This defence response can be enhanced therapeutically. We therefore want to define exactly how LIF enhances myelin survival. We have measured the response to LIF in myelin-producing cells, and have discovered that it strongly stimulates the production of the small protein galanin. We will now assess if galanin itself protects myelin and myelin-producing cells, and we will test this both in isolated cells and whole animal models. If galanin production is a major mechanism by which the body tries to limit the damage from abnormal inflammation during MS, then medications that mimic the action of galanin (which are already under development for different reasons) could become a major new therapy for Multiple Sclerosis.Read moreRead less
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
A Novel Lipid Sensitive Kinase And Its Role In Obesity-induced Inflammation And Insulin Resistance.
Funder
National Health and Medical Research Council
Funding Amount
$560,045.00
Summary
It is now apparent that obesity leads to chronic low grade inflammation which results in insulin resistance or pre-diabetes. The mechanisms that link obesity-induced inflammation to insulin resistance are not well understood, but involve lipid oversupply. We have preliminary data identifying that a protein, not known to previously play a role in metabolic diseases, is a critical mediator of lipid-induced inflammation. We will investigate the clinical potential of blocking this protein.
Controlling Neuroinflammation In Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$639,577.00
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, with 269,000 Australians currently diagnosed with AD and is expected to soar to about 981,000 by 2050. AD accounts for greater than 60% of all cases of dementia. This grant investigates the role that neuroinflammation plays in the progression and exacerbation of AD and will identify new therapeutic strategies to combat this insidious disease.
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.
Understanding Neuroinflammation In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,043,216.00
Summary
This project opens a new line of enquiry into the cellular signalling mechanisms involved in the progression of AD and establishes whether targeting the involvement of type-1 IFN signalling influences the evolution of AD. New and novel approaches are clearly required to treat AD. Importantly, we believe that neuroinflammation is common to all causes of dementia and targeting the neuroinflammatory pathways has much wider implications than targeting the primary causative pathway.