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Islet Cell Replacement Initiative ResearchersIslet Cell Replacement Initiative Researchers On November 20, 2003 the American Diabetes Association Research Foundation announced the selection of seven researchers to receive funding from the American Diabetes Association National Research Program's Islet Cell Replacement Initiative for people with type 1 diabetes. These research awards support investigators who are developing basic science, clinical and translational research focusing on islet (insulin-producing) cell replacement in type 1 diabetes. The work of these researchers could lead to procedures that would ultimately restore the body's ability to produce insulin. The seven award recipients include:
Charles Burant, MD, PhD University of Michigan Ann Arbor, Michigan January 2004 - December 2007 Focus: Stem Cell Manipulating TGF beta signaling to isolate and characterize a replicating duct-derived adult islet precursor The TGF beta-family of proteins regulates the growth and differentiation of many cell types. We have made a mouse with a disruption in a specific molecule that is necessary for TGF beta signaling. These mice show a 5-fold enlargement of normal looking islets and build up what appear to be islet precursor cells. Cultures grown from pancreatic ductal cells of these mice show enhanced growth differentiation into insulin-expressing cells. We believe that the enhanced ability of these cells to grow in culture can be used to isolate the adult islet stem cell. Using unique tools and genetically engineered mice (transgenic mice) we will determine the best conditions for the growth of stem cell and their development into insulin producing cells. We will determine the genetic profile of these cells and determine whether the growth and self-renewal of these cells changes with age. Finally, we will determine if the cells can be used to treat an animal model of type 1 diabetes. By proving that manipulating the TGF beta signaling in islet precursor cells results in enhanced expansion, we may be able to use these tools to isolate and expand human islet precursor cells in order to create large numbers of islets for transplantation. Hengjiang Dong, PhD Mount Sinai School of Medicine New York, New York January 2004 - December 2006 Focus: Genetic Engineering Development of insulin gene therapy for type 1 diabetes Type 1 diabetes is caused by the lack of insulin production in the pancreas. Insulin gene therapy is being developed as an alternative insulin replacement therapy for it offers great potential for achieving long-term blood glucose control without causing immune rejection. Here the insulin gene is delivered through a gene vehicle to the liver, such that insulin will be produced in liver cells and released into the blood stream. We have provided proof-of-principle that sustained insulin production at a basal level in the liver is sufficient to prevent the development of ketones in the urine and relieve diabetes symptoms in diabetic animals. To improve this procedure, we propose to control insulin production to achieve insulin release in a glucose-dependent manner. In other words, we will use the natural glucose and insulin response mechanisms in the liver to generate a regulated system, in which insulin production will be stimulated when blood sugar is high and suppressed when blood sugar is low. Our hypothesis is that this highly regulated system will provide control of blood sugar without low blood sugar episodes caused by production of too much insulin. We will test this system in diabetic animals for its safety and efficacy in blood sugar control. Marc Garfinkel, MD University of Chicago Chicago, Illinois January 2004 - June 2008 Focus: Xenografts Study of a novel method of islet encapsulation: Inverted selective withdrawal Type 1 diabetes is caused by failure or cells within the pancreas (islets) to make insulin in response to high sugar levels in the blood. Islet transplantation from non-living donors has been shown to be effective in treating type 1 diabetes, but islets are in limited supply, and patients who receive transplants of islets must take medications to prevent the body's immune system from rejecting the transplanted cells. One method of preventing rejection without medications, and possibly using cells from animals (unlimited supply) is to envelop them in thin coats of gelatin-like material (microencapsulation). We have been working on a new method of microencapsulation, which involves creating a layer between two liquids, like oil and water, and applying suction above the layer to generate a thin spout of the lower liquid. This spout then breaks into small beads, surrounding particles (or islets) contained in the water layer. These beads are then exposed to a process that causes them to gel. We propose experiments to show whether islets microencapsulated by this method will reverse diabetes without rejection-preventing medications. If successful, this method may be further developed to allow transplant of human or even animal tissue without rejection. Michael German, MD University of California San Francisco, California January 2004 - December 2007 Focus: Stem Cell Transformation of progenitor cells to beta cells A cure for people with type 1 diabetes, and for many people with type 2 diabetes, will require the replacement of the beta cells, the cells in the pancreas that produce insulin. In this application, we propose to apply new insights into how beta cells form during normal development, to the problem of producing beta cells for patients with diabetes. The beta cells form from progenitor cells during the fetal development of the pancreas. The pathway from progenitor cell to sophisticated beta cell is a step-wise progression involving the orderly activation of specific genes. This laboratory, along with others, has recently identified many of these genes and the mechanisms that control their sequential activation. What we are proposing is to use these genes to force progenitor cells in the culture dish to mature into beta cells. The proposed experiments will determine what minimal set of genes are required for the production of beta cells, and what source of ells is both capable of responding to these genes and practical for clinical use. This is a high risk project; there are many reasons why we may fail. But if we succeed, we will have developed a safe and renewable source of beta cells for people with diabetes. Luca Inverardi, MD University of Miami School of Medicine Miami, Florida January 2004 - December 2007 Focus: Stem Cell Culture, characterization and differentiation of fetal pancreatic progenitor cells Transplantation of pancreatic islets has been shown to restore the ability of type 1 diabetic patients to tightly regulate blood glucose levels without the need for daily insulin injections. In recent years, this therapeutic approach has enormously benefited from the development of a new protocol of immunosuppression that does not utilize cortisone. Promising results from several ongoing clinical trials (including our own at the University of Miami) demonstrate the feasibility of this approach. However, the current shortage of islets has limited the widespread implementation of this therapy. One possible solution to this problem is the use of stem cells obtained from fetal pancreata that can be: 1) expanded to great numbers, and 2) induced to become islet cells prior to transplantation. Our ultimate goal is to isolate such stem or progenitor cells, which are contained in the pancreas, and develop the necessary conditions for their expansion and subsequent specification to become insulin-producing cells suitable for human transplantation. To do so, we will study and later recapitulate "in vitro" the critical events that normally occur in the natural development of the pancreas. Success in these studies might contribute to solve the current problem of scarce availability of islets from cadaveric donors. Paul Robbins, PhD University of Pittsburgh Pittsburgh, Pennsylvania January 2004 - September 2007 Focus: Stem Cell Development of methods for insulin gene transfer to K cells in vivo Transplantation of donated human islets has been shown to be an effective approach to treat diabetes and eliminate the need for insulin injections in patients. However, the source of tissue of cells that can produce insulin is currently inadequate to offer widespread treatment to diabetic patients. Therefore, there is a significant need to identify other sources of insulin secreting tissue. A specific type of cell that is found in the gut, the K-cell, can respond to glucose in the appropriate manner, releasing insulin in a way similar to insulin release from islets. Thus we are exploring approaches to transfer the insulin gene to the layer of epithelial cells lining the gut where K-cells reside and which is readily accessible. We hypothesize that engineering normal endogenous K-cells in the gut by gene transfer into insulin-producing cells could be an effective approach to treat diabetes. Thus the focus of this proposal is to identify methods for optimized gene delivery to K-cells or K-cell precursor cells in the gut following oral delivery. The successful completion of the proposed studies will result in improved methods for delivery of the insulin gene to K-cell or K-stem cells in the gut. Ji-Won Yoon, PhD Finch University of Health Sciences Chicago, Illinois January 2004 - December 2006 Focus: Genetic Engineering Replacement of beta cells for the treatment of autoimmune type 1 diabetes Type 1 diabetes is caused by the autoimmune destruction of insulin-producing pancreatic beta cells. Research on islet transplantation has made progress toward a cure for the disease; however, the availability of human islet is limited and life-long immunosuppression is required to prevent transplant rejection. We recently developed a method for the regeneration of insulin-producing cells in pancreatic islets using gene therapy. We developed a gene construct that produces a beta cell growth factor, betacellulin, which can induce the generation of insulin-producing, beta-like cells. A single injection of this gene construct resulted in the complete remission of diabetes in chemically induced diabetic mice. The first specific aim is to find how the betacellulin can induce the generation of insulin-producing, beta-like cells. One concern about the cure of diabetes using a beta cell regeneration approach is reattack of the newly formed beta-like cells by pre-existing autoimmune cells. We recently found that a human hormone, human choriogonadotropin (hCG), can prevent autoimmune diabetes in NOD mice, an animal model of human autoimmune diabetes, by blocking the autoimmune attack. Our second specific aim is to cure autoimmune diabetic NOD mice by inducing insulin-producing cells in the pancreas with betacellulin and blocking autoimmune attack with hCG. |
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