Molecular Analysis Of Pathways In Diabetes (MAPDB) Study
Funder
National Health and Medical Research Council
Funding Amount
$3,348,000.00
Summary
The sequence of human genome provides a complete part-list of the genes and proteins that make our bodies. A most unknown subset of these parts work together in molecular pathways that underpin susceptibility and resistance to Type 1 diabetes and its complications. The MAPDB study will link patients, families, doctors, genome experts, immunologists, physiologists, statisticians and data base programmers together to illuminate these molecular pathways. In particular, the study will reveal genes a ....The sequence of human genome provides a complete part-list of the genes and proteins that make our bodies. A most unknown subset of these parts work together in molecular pathways that underpin susceptibility and resistance to Type 1 diabetes and its complications. The MAPDB study will link patients, families, doctors, genome experts, immunologists, physiologists, statisticians and data base programmers together to illuminate these molecular pathways. In particular, the study will reveal genes and pathways that medicate protection from diabetes and its complications - either by inhibiting T cell responses to pancreatic beta cells, protecting or regenerating beta cells in the face of metabolic or immunologic stress, or protecting eyes and kidneys from the damaging effects of high blood glucose. By identifying genes and proteins with these functions, the study will enable new treatments to be developed aimed at augmenting these protective pathways, to prevent diabetes starting in children at risk, and to preserve beta cell mass, protect transplanted stem cells or beta cells, and prevent eye and kidney damage in people already affected by Type 1 diabetes. Genes and proteins that are needed for T cell attack on beta cells will also be revealed. This information will enable new treatments to be developed that block these processes, to prevent diabetes from starting, to preserve beta cell mass and to prevent destruction of transplanted stem cells or beta cells. The MAPDB study will also identify different versions-alleles- of many of the genes in the pathways described above. Particular combinations of these gene alleles will be defines that can identify people at high risk of developing Type 1 diabetes, risk of cell or islet transplantation rejection, or at most risk for eye-kidney complications. Different gene combinations may be found that allow different kinds of Type 1 diabetes to distinguished. By creating ways to identify and distinguish people's individual risk, the study will yield diagnostic tests to enable new treatments and clinical trials to be targeted.Read moreRead less
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