In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune syste ....In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune system and to test ways of protecting beta cells from these mechanisms. Because of the inaccessibility of the pancreas to study (particularly biopsy) in humans with diabetes, much of the proposed work will be carried out in b cells derived from non-obese diabetic (NOD) mice, the best available mouse model of type 1 diabetes. It is clear from the literature that a molecule called perforin found in cytoxic T lymphocytes (CTL) is a major, if not the major, mechanism the immune system uses against b cells. For this reason we will try to better understand the interaction between b cells and perforin and ultimately design ways of them from perforin-mediated cell death. It is equally clear that there are other mechanisms besides perforin that can cause b cell death and the program will also address discovery of these mechanisms and new ways to block them. Beta cells in NOD mice will be protected from perforin or other mechanisms by the addition of protective genes or removal of harmful genes using transgenic knockout technology. Addition or removal of genes involved in cell death can be done systematically and each protocol tested using NOD mouse model. The process of cell death that b cell undergo in type 1 diabetes is called apoptosis. Apoptosis is a general mechanism by which cells of all types die. Experts in the biology of apoptosis and perforin are important members of the program, providing the opportunity to translate the latest advances in cell death research to diabetes. This research addresses several of the specific research areas of interest to JDRF. It focuses on the prevention of b cell death in individuals with type 1 diabetes receiving islet transplants. It may be applicable in the future to protection of stem or precursor cells that have been differentiated into b cells or even to devising strategies to prevent the development of diabetes.Read moreRead less
Cancers arise as a result of the impairment of critical cellular processes following the mutation of important regulatory genes. I am a molecular biologist and I study how the proteins of the Bcl-2 family regulate apoptosis, a process of cell death essential to maintain homeostasis in multicellular organisms, with the aim of designing drugs to kill cancer cells selectively. I am also interested in discovering new genes involved in the development of cancer using new genomics technology.
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
Uncovering The Basis Of Inflammatory And Immunodeficiency Diseases
Funder
National Health and Medical Research Council
Funding Amount
$15,718,075.00
Summary
A world-class team from 3 institutions, spanning disciplines of clinical and experimental immunology, therapeutics, signalling and genetics, will identify how immune and inflammatory responses are controlled in both health and disease. The major outcomes of this work will be the generation of new knowledge, concepts and approaches to diagnose, prevent and treat the major human health problems of autoimmune diseases, inflammation, allergy and immunodeficiency.
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
Generation Of Mouse Models To Study The Roles Of Different Bcl-2 Family Members In The Regulation Of Apaptosis
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
Programmed cell death, or apoptosis, is required for the removal of infected, damaged or unwanted cells and its disrupted regulation is implicated in cancer, autoimmunity and degenerative disorders. The Bcl-2 family of proteins are key regulators of apoptosis. We propose to generate several mouse models to better understand the relationships between the different members of the Bcl-2 family in an effort to control this pathway for therapeutic purposes.
The majority of stroke results from focal brain infarction, followed by substantial secondary excitotoxic damage in the surrounding areas. Tau has been shown to contribute to excitotoxicity and neurodegeneration in mouse models of Alzheimer’s disease (AD). Preliminary data show that tau reduction also protects against excitotoxic damage after experimental stroke. We aim to dissect the molecular mechanisms of stroke using a tau-deficient mouse model.
Identifying Novel Antimalarial Targets Using ENU Mutagenesis In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$760,170.00
Summary
Malaria is estimated to cause 1.2 million deaths per year. The malarial parasite has developed resistance to most drugs and new drugs are needed. We aim to mimic the protective red blood cell diseases common in human populations in malarial endemic areas by identifying host targets that are important in parasite growth.
TAF8 is a small protein that is associated with the general transcriptional apparatus. TAF8 is not an essential part of the general transcriptional machinery, but rather a regulatory molecule that appears to dictate how the machinery is used to express different genes. The absence of TAF8 leads to expression of genes controlling cell death. Since the avoidence of cell death is essential to the development of cancer these results will lead to a better understanding of how cancer develops.