The Role Of Nalp1 In Autoimmune Disease And Innate Immune Defense As Determined By Murine Genetic Deletion.
Funder
National Health and Medical Research Council
Funding Amount
$320,237.00
Summary
The innate immune system is a critical barrier against invading microorganisms, however when improperly regulated it can lead to autoimmune disease. Nalp1 is a protein that is important for innate immune recognition of anthrax infection, and is also involved in susceptibility to vitiligo and associated autoimmune diseases. This project seeks to create mice that are deficient for the gene encoding Nalp1 so as to further study the role of this protein in innate immune defense and autoimmunity.
A Functional Genomic Approach To The Genetics Of Autoimmune (type A) Gastritis
Funder
National Health and Medical Research Council
Funding Amount
$467,640.00
Summary
The thymus produces white blood cells which defend the body from infections and cancer. Unfortunately, these white blood cells can also cause disease if they target the body's own tissues. These disesaes are called autoimmune diseases, and an example of such a disease is autoimmune (type A) gastritis, in which the white cells target the acid-producing cells of the stomach. The resulting damage can lead to the development of pernicious anaemia (vitamin B12 deficiency) and cancer of the stomach. T ....The thymus produces white blood cells which defend the body from infections and cancer. Unfortunately, these white blood cells can also cause disease if they target the body's own tissues. These disesaes are called autoimmune diseases, and an example of such a disease is autoimmune (type A) gastritis, in which the white cells target the acid-producing cells of the stomach. The resulting damage can lead to the development of pernicious anaemia (vitamin B12 deficiency) and cancer of the stomach. This project studies a mouse model of autoimmune gastritis with the aim of identifying the genes that encode susceptibility to the disease in this model. Ultimately, this information should help us to devise therapies that can be applied to the clinical situation. We have previously identified the locations of the genes which are responsible for causing gastritis in these mice. Two of them are very close together on one chromosome and appear to be very important because they have the strongest effects. Furthermore, there is some evidence that these genes may also be involved in determining susceptibility to diabetes and lupus. This project aims to further characterise these genes by locating them more exactly and by examining their effect on mice not normally prone to gastritis.Read moreRead less
Apoptotic Pathways In Pancreatic Beta Cells Leading To Type 1 Diabetes And Transplant Rejection
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
The destruction of insulin-producing beta cells in the pancreas by immune cells leads to the need for daily insulin injections in patients with type 1 diabetes. This project aims to understand how beta cells are destroyed. A knowledge of the process by which this occurs will indicate ways we can protect these cells. Our previous work has suggested strategies that may protect beta cells, and we aim to test these. Such protection may eventually allow beta cell replacement by transplantation.
Building a death-defying islet beta cell Type I diabetes results when the cells that produce insulin (the islet beta cells) are killed by the immune system. The beta cell, like any other cell in the body, can be induced to die by activation of a process that leads to cell suicide. During this process, enzymes dismantle the structure of the cell and the remains are eaten by neighboring cells. In diabetes, the stimulus for beta cell suicide is provided by a number of agents most of which are made ....Building a death-defying islet beta cell Type I diabetes results when the cells that produce insulin (the islet beta cells) are killed by the immune system. The beta cell, like any other cell in the body, can be induced to die by activation of a process that leads to cell suicide. During this process, enzymes dismantle the structure of the cell and the remains are eaten by neighboring cells. In diabetes, the stimulus for beta cell suicide is provided by a number of agents most of which are made by the T cells of the immune system. Our aim is to interfere with this cell suicide process and engineer a beta cell that can resist T cell attack. Because genetically manipulated mice provide the flexibility we need to add and subtract genes from the beta cell we will use them as a model to build a death-defying beta cell. We will investigate three strategies. Firstly, cells will be engineered to express a molecule (CD30 ligand) which recognizes a protein on the surface of the attacking T cells and in so doing, sends a signal to the T cells to stop proliferating. Secondly, we will remove proteins (CD95, TNFRI) from the surface of the beta cell, that attacking T cells use to set in motion the cell suicide process. Thirdly, we will engineer beta cells that express inside themselves, cell death inhibitor proteins (Bcl-2, CrmA, p35) that can prevent the automatic process of cell suicide. It is our hope that studies with death-defying beta cells will find a new way to manipulate islet tissue for transplantation. In patients with diabetes, the beta cells have all been destroyed but the attacking T cells still remain. As a result, transplants of new beta cells are rapidly damaged. Beta cells that can resist ongoing immune attack may survive well enough to reverse the symptoms of diabetes. The success of this research could have an impact on a cure for diabetes.Read moreRead less
Dissecting The Role Of The Lyn Tyrosine Kinase In B Cell Differentiation And The Development Of Autoimmunity.
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune diseases include more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more effective treatments. The Lyn tyro ....The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune diseases include more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more effective treatments. The Lyn tyrosine kinase is a member of a family of genes that participate in transmitting information across the cell membrane. This enzyme is expressed in blood cells, and is involved in mechanisms pertaining to infection, immunity and allergic responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn (Lyn-deficient mice) and one that expresses an activated form of the Lyn enzyme (Lyn-up mice). We have found that both strains of mice develop autoimmune disease with characteristics similar to the human autoimmune disease systemic lupus erythematosus (SLE). These studies suggest that Lyn is an important severity gene in autoimmunity. In this study we will examine in detail the role that Lyn plays in B cell development, function and autoimmunity, and we intend to identify the pathways that lead to autoimmune disease in Lyn mutant mice. On completion of these studies we will have developed a catalogue of the molecules and pathways perturbed in Lyn mutant mice. These studies will greatly improve our knowledge and understanding of the mechamisms behind certain autoimmune diseases, and may indeed lead to improved diagnosis, prognosis and treatment of patients with these conditions.Read moreRead less