My research is directed to the prevention of diabetes, across the spectrum from type 1 to type 2 diabetes. It is based on understanding immune-inflammatory mechanisms that contribute to dysfunction and death of pancreatic insulin-secreting beta cells and tissue resistance to the action of insulin. I study these mechanisms in rodent models and in humans in the context of relevant environmental factors and genes, with the aim of manipulating them for therapeutic benefit.
An Autoantibody In Type 1 Diabetes That Mediates Autonomic Complications
Funder
National Health and Medical Research Council
Funding Amount
$254,591.00
Summary
Type 1 diabetes is a chronic autoimmune disease characterised by destruction of insulin producing cells in the pancreas. One of the most common and serious complications of type 1 diabetes is disruption of the autoimmune nervous system, and once symptoms appear the 5-year mortalityrate is approximately 50%. Symptoms of autonomic dysfunction can be extensive, and involve the stomach, intestine, bladder, heart and reproductive organs. Currently, the management of autonomic dysfunction remains prim ....Type 1 diabetes is a chronic autoimmune disease characterised by destruction of insulin producing cells in the pancreas. One of the most common and serious complications of type 1 diabetes is disruption of the autoimmune nervous system, and once symptoms appear the 5-year mortalityrate is approximately 50%. Symptoms of autonomic dysfunction can be extensive, and involve the stomach, intestine, bladder, heart and reproductive organs. Currently, the management of autonomic dysfunction remains primative due to our poor understanding of the mechanisms underlaying the disease. Recent work from our group has identified an excitatory autoantibody (an antibody against the self) to calcium channels in patients with type 1 diabetes. The anti-calcium channel autoantibody profoundly disrupts gut and bladder function by interfering with autonomic regulation of smooth muscle within these organs. The anti-calcium channel autoantibody is the first functional autoantibody to be detected in type 1 diabetes, and represents a conceptual advance in our understanding of immune mechanisms in this disease. Using animal models and a panel of novel, functional assays of colon, stomach and bladder we will investigate how the anti-calcium channel autoantibodies contribute to autonomic dysfunction in type 1 diabetes. Understanding the mechanisms by which this autoantibody effects autonomic regulation of organ function will enable the development of new therapeutic strategies for better management of patients.Read moreRead less
Our work package looks at Control of pathogenic autoimmunity through regulation by the autoimmune regulator gene (AIRE) in thymic epithelial cells� and has a major influence on work package no 1). __ Design of specific tolerogenic peptide therapies based on the identification of tissue-restricted self-antigen epitopes escaping tolerance�, but interacts either directly or indirectly with all other packages
My research is directed to the prevention of type 1 diabetes, based on understanding immune-inflammatory mechanisms that contribute to dysfunction of insulin-secreting beta cells and tissue resistance to the action of insulin. I study these mechanisms in rodent models and in humans with the aim of manipulating them for therapeutic benefit. I am particularly interested in understanding environment-gene interactions mediated by epigenetic modifications.
Role Of Heparan Sulfate, Heparanase Inhibitors In The Development And Prevention Of Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$3,242,772.00
Summary
Our recent studies have shown that a special protein (an enzyme called heparanase) and the special carbohydrate (heparan sulfate or HS) that it degrades, play a previously unrecognised role in the development of Type I diabetes (T1D) in mice. We will explore whether destructive immune cells use heparanase to damage insulin-producing islets and deplete them of HS, resulting in islet cell death and T1D. We will develop new agents to inhibit this damage, prevent T1D and protect islet transplants.
De Novo Mutations And The Pathogenesis Of Childhood-onset Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,406,510.00
Summary
This project aims to reveal the gene abnormalities that cause devastating autoimmune diseases to develop in some children, such as Type 1 diabetes, juvenile arthritis and autoimmune destruction of blood cells. The project will use new technologies to identify alterations in the DNA sequence of a child compared to either of their parents, and to test suspicious DNA alterations in laboratory mice in order to understand the gene effects and evaluate new treatments.
Analysis Of Human CD4+ T-cell Responses To Epitopes Formed By Peptide Fusion In The Pathogenesis Of Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$1,239,989.00
Summary
Type 1 diabetes is caused by immune-mediated destruction of the insulin-secreting beta cells. Recently we discovered new targets ‘seen’ by the immune system that may explain why the immune system causes type 1 diabetes. Here we will determine if responses to these targets cause type 1 diabetes. This is important because it tests a new idea and our results will have a major impact on efforts to develop new therapies for type 1 diabetes an other autoimmune diseases.
Identifying The Underlying Mechanisms Responsible For The Generation Of Pathogenic B Cells In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$163,755.00
Summary
Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are r ....Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are responsible for most of the damage to the beta cells in T1D. Recent work in this model, however, has demonstrated that another class of immune cell, termed B cells, also play an important role in T1D as NOD mice made deficient in these cells no longer develop disease. In addition to producing antibodies, B cells are one of the few cell types which are able to take up and present protein fragments in a form recognizable to T cells. Normally, this only leads to the activation of T cells recognising foreign insults, like viruses or bacteria, resulting in their destruction. We have shown that a dangerous population of B cells can arise in NOD mice that can specifically take up beta cell proteins and present them to the T cells, which subsequently become armed to recognise and destroy the beta cells. Just like T cells, B cells that recognize the body's own proteins are normally eliminated in healthy mice and human individuals. This research proposal aims to determine the faulty immune mechanisms that give rise to the beta cell specific B cells in NOD mice. We have also set out to identify the diabetes susceptibility genes which control the generation of this dangerous population of B cells in this model. By understanding how these dangerous B cells are generated in NOD mice, we hope to form the basis for new therapies aimed at inhibiting these cells from forming in T1D susceptible humans, thus preventing the disease at an early stage.Read moreRead less
The Role Of The T Cell Protein Tyrosine Phosphatase In Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$654,725.00
Summary
Autoimmune diseases such as type 1 diabetes, Crohns disease & rheumatoid arthritis collectively affect ~5% of Australians & are associated with the immune system attacking the body’s organs as if they were a foreign infection. Genetic studies in humans & animal studies point towards the enzyme TCPTP being important in the prevention of autoimmunity. This proposal will define the molecular & cellular pathways by which TCPTP prevents autoimmunity.
The Molecular Basis Of Human CD4+ T-cell Responses In Autoimmune Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$656,498.00
Summary
Over 120,000 Australians currently suffer from type 1 diabetes. This incurable disease typically strikes in childhood or adolescence and is caused by the immune system destroying the cells which make insulin. This project aims to determine how and why the insulin producing cells are recognized by the immune system. Eventually this work will lead to new vacccines to prevent the immune system from destroying the insulin producing cells.