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PI Name: Brian David Brown, Ph.D.
Institution: Mount Sinai School of Medicine of NYU
Project Number: DP2 DK083052-01
Project Title: Novel Strategy to Induce Islet Protective Regulatory T Cells and Prevent Diabetes
Abstract: Type I diabetes is an autoimmune disorder in which insulin-producing cells are destroyed by the immune system. Once these cells are destroyed patients must take replacement insulin to survive. More then 300,000 Americans have type I diabetes, and another 30,000 will be diagnosed this year alone. Scientific research has enabled improved methods for predicting who will develop type I diabetes, and for making early diagnosis, but despite these important breakthroughs, there is currently no way of stopping the progression of the disease. We intend to change this by developing a new type of vaccine that can be used to teach the immune system not to attack insulin-producing cells. Recently, we developed a new platform for regulating the expression of exogenously delivered genes, such as those used for gene therapy. This platform utilizes a novel class of genes, known as microRNA. Here, we will exploit this technology to create a new type of DNA vaccine that can be used to boost immunological tolerance to a specific protein, and thereby prevent the type of autoimmune response responsible for type I diabetes. Studies will initially be carried out to determine if we can target our DNA vaccine to specific cell types that have a physiological role in maintaining immunological tolerance. Following these studies, we will assess whether our approach can induce tolerance to insulin, one of the proteins targeted by the immune system in diabetics. Finally, we will evaluate the effectives of our approach for preventing type I diabetes in a mouse model of the disease. Public Health Relevance Statement: The novel vaccine being developed in this proposal will have important relevance to public health as it will provide a means for preventing type I diabetes in humans.
PI Name: Deyu Fang, Ph.D.
Institution: University of Missouri School of Medicine
Project Number: DP2 DK083050-01
Project Title: A Novel Target for Type 1 Diabetes
Abstract: Type 1 diabetes (T1D) is particularly tragic because it usually starts in childhood and its effects worsen with time. This autoimmune disease is caused by self-attacking immune cells that result in the permanent destruction of the insulin-producing β-cells in the pancreas. In healthy humans, most, if not all, self-attacking immune T cells are generally eliminated during development, and, if any leaking occurs, these cells are tolerized in the peripheral lymphoid tissues. Therefore, failing to induce the tolerance of T cells, which attach insulin-producing β-cells, is crucial for type-1 diabetes. However, the molecular means by which T-cell tolerance is induced has remained an immunological puzzle for decades. Here we report that Sirt1, a type III histone deacetylase, is required for T-cell immune tolerance. Genetic disruption of Sirt1 function results in abnormally elevated immune responses and a break-down of T-cell peripheral tolerance. As a consequence, Sirt1-/- mice develop spontaneous autoimmunity. We have proposed that Sirt1-deficency may enhance diabetes development, and that activation of Sirt1 by small molecules like resveratrol can potentially be used to treat type-1 diabetes by inhibiting β-cell-attacking autoimmune T cells. Indeed, results from our preliminary studies indicate that resveratrol protects non-obesity diabetic mice from diabetes. A patent application for the use of Sirt1 activators in combating T1D in humans is currently being processed, and a manuscript describing our findings is under revision for publication by Cell. Therefore, this proposal aims to determine the molecular mechanisms underlying Sirt1 function as an anergic factor of T-cells, and to investigate how mis-regulated Sirt1 is involved in the development of T1D. We will also further examine the effects of resveratrol on preventing/treating T1D. Since FDA has approved the human use of resveratrol, we expect to develop a translational research program for the treatment of diabetes in humans with the support of this finding. Public Health Relevance Statement: It is anticipated that this proposed research could resolve the immunological puzzle of T cell tolerance and result in potential therapeutic reagents for type 1 diabetes in humans.
PI Name: John M. Hollander, Ph.D.
Institution: West Virginia University School of Medicine
Project Number: DP2 DK083095-01
Project Title: Mechanisms of Diabetic Cardiomyopathy: Mitchondria Subpopulations
Abstract: One to two million people in the United States, suffer from type 1 diabetes mellitus. Diabetic cardiomyopathy is an impairment of heart muscle that exists independently of coronary artery disease, and is associated with diabetes mellitus. Diabetic cardiomyopathy is characterized by contractile dysfunction which contributes to myocardial infarction and heart failure. Hyperglycemia associated with diabetes mellitus, increases reactive oxygen species (ROS) generation. Because the mitochondrion is the primary site for ROS generation, determination of how mitochondria are affected by diabetes mellitus is crucial for understanding the pathogenesis. Examination of mitochondria is complicated by the fact that two mitochondrial subpopulations are present in the cardiomyocyte, interfibrillar mitochondria (IFM), which situate between the contractile apparatus and subsarcolemmal mitochondria (SSM) that exist beneath the plasma membrane. Currently, it is unclear how spatially distinct mitochondrial subpopulations are effected by diabetes mellitus making it difficult to ascertain their specific contribution to diabetic cardiomyopathy. Our long-term goal is to elucidate the mechanisms involved in the pathogenesis of diabetic cardiomyopathy as a prerequisite to the development of therapeutics designed to lessen cardiac complications associated with diabetes mellitus. The central hypothesis of this application is that cardiac IFM are at greater risk from diabetic insult than SSM. The objectives of this application are to determine the effect of diabetic insult on spatially distinct mitochondrial subpopulations, identify key factors that contribute to dysfunction in specific mitochondrial subpopulations, and to develop therapeutics that target spatially distinct mitochondria subsets. Public Health Relevance Statement: The proposed studies will enhance our understanding of the pathogenesis of diabetic cardiomyopathy providing information regarding targets for therapeutic interventions that will aid in the treatment of type 1 diabetes mellitus. The genesis of therapeutic tools designed to treat specific mitochondrial subsets will enhance therapy option flexibility, and provide a better means for the treatment of loci at risk from diabetes mellitus.
PI Name: Kenneth W. Liechty, M.D.
Institution: Children’s Hospital of Philadelphia
Project Number: DP2 DK083085-01
Project Title: Extracellular Matrix Structure and Function in Diabetic Wound Healing
Abstract: Chronic non-healing wounds represent a significant complication of diabetes, resulting in significant morbidity, lost productivity, and healthcare expenditures. The rising incidence of obesity and diabetes has increased the number of people at risk for diabetic wounds. Despite the enormous impact these chronic wounds have, effective therapies have been lacking. The correction or prevention of diabetes impaired wound healing has far reaching consequences on patient outcomes, healthcare expenditures, and public health. Normal wound healing is an intricate process involving multiple growth factors, cell types, and complex signaling interactions. Alterations in growth factor and chemokine production, cellular recruitment, angiogenesis, extracellular matrix production, and wound contraction have all been shown to contribute to the diabetic wound healing impairment. While these factors have been implicated as potential etiologies in the diabetic wound healing impairment, very little information is available about the biomechanical properties of the diabetic dermis prior to injury or following wound closure. Tissues with inferior biomechanical properties are structurally and/or materially weakened and are at high risk for injury, degeneration, failure or other pathologies. We have recently demonstrated that the diabetic dermis has inherently inferior biomechanical properties at baseline, prior to injury, which puts the tissue at increased risk for damage and/or failure when compared to non-diabetic skin. We have recently demonstrated that treatment of diabetic wounds with stromal progenitor cells (SPC) or lenti-viral overexpression of SDF-1α, a chemokine involved in progenitor recruitment, can correct the impairment in diabetic wound closure. We hypothesize that SPC, or strategies to increase progenitor recruitment, can correct the inferior biomechanical properties of the diabetic dermis and improve the subsequent wound healing following injury. In addition, characterization of the mechanisms involved in SPC or lenti-SDF-1α mediated correction of the diabetic wound healing impairment will provide further insight into strategies to modify the diabetic wound healing response. Public Health Relevance Statement: Non-healing diabetic wounds represent a major health problem. This project’s goal of development of a treatment to improve the strength of diabetic skin either at baseline, to prevent injury, or following injury, to speed healing and prevent recurrent injury, would have far-reaching consequences on patient outcomes, healthcare expenditures, and overall public health.
PI Name: Xunrong Luo, M.D., Ph.D.
Institution: Northwestern University
Project Number: DP2 DK083099-01
Project Title: ECDI Coupled Cells for Tolerance in Allogeneic Islet Cell Transplantation for T1D
Abstract: Human allogeneic islet cell transplantation as a therapy for cure for type 1 diabetes can be significantly improved if the deleterious effects of indefinite immunosuppression, particularly with their direct toxicity to β cells, can be eliminated. Therefore, simple and effective donor-specific tolerance induction in such autoimmune diabetic hosts would be highly desirable. We have recently developed a novel tolerance regimen using i.v. infusion of donor splenocytes that are treated with a chemical cross-linker termed 1-ethyl-3-(3’-dimethylaminopropyl)-carbodiimide, or ECDI, and found that in the absence of any immunosuppression, this regimen is highly efficient in inducing durable donorspecific tolerance in allogeneic islet cell transplantation in the chemically-induced (streptozotocin), non-autoimmune diabetes model. However, considerable obstacles exist in translating this methodology to a model harboring both alloimmunity and autoimmunity, a model that is highly clinically relevant to patients with type 1 diabetes receiving deceased donor islet transplantation. This application proposes to take an integrated approach to identify crucial cellular components and signaling pathways required for tolerance by this protocol, as well as critical differences that exist in the autoimmune diabetic hosts responsible for the ineffective tolerance induction. Public Health Relevance Statement: The ultimate goal of this study is to engineer novel tolerance regimen that is tailored to the specifics of islet allograft delivery, and is efficient and clinically feasible for human allogeneic islet cell transplantation. Successful completion of the proposed study will have significant impact on therapeutic options for patients with type 1 diabetes.
PI Name: Edward E. Mitre, M.D.
Institution: Uniformed Services University of the Health Services
Project Number: DP2 DK083131-01
Project Title: Protection Against Type 1 Diabetes by Parasitic Helminths
Abstract: As Type 1 diabetes is caused by autoimmune destruction of insulin-producing β-islet cells, modulation of the ongoing autoimmune response in recently diagnosed patients may inhibit progression of the disease. A significant obstacle, however, is that current strategies of immunosuppression for treatment of autoimmune diseases often increase patient susceptibility to infections. We hypothesize that the immunoregulatory responses induced by chronic helminth infections can suppress the inappropriate inflammation of autoimmune disorders without significantly impairing the ability of the immune response to fight invasive pathogens. While patients with chronic helminth infections are not clinically immunocompromised, both human and animal studies demonstrate that chronic parasitic worm infections are protective against autoimmune diseases. Recently, our laboratory has demonstrated that infection of non-obese diabetic (NOD) mice with Litomosoides sigmodontis, a tissue-invasive parasitic filarial worm of rodents, protects against the development of diabetes. We have also shown that this helminth-mediated protection is associated with an increase in natural Tregulatory cells. Live infection is not required for protection, as injection of a crude homogenate of L. sigmodontis antigens also protects against diabetes. The major objectives for this proposal are to determine the mechanisms by which L. sigmodontis protects against the development of Type 1 diabetes in NOD mice and to identify the specific molecules of L. sigmodontis that can induce this protection. We also plan to determine the potential therapeutic utility L. sigmodontis-derived therapies may have. Specifically, we plan to assess the degree to which L. sigmodontis infection and antigen administration can reverse established disease and the impact these interventions have on the immune system’s ability to protect against invasive pathogens. Public Health Relevance Statement: The goal of this project is to develop new therapies for Type 1 diabetes that do not substantially compromise the ability of the immune system to protect against invasive pathogens.
PI Name: Cherie L. Stabler, Ph.D.
Institution: University of Miami
Project Number: DP2 DK083096-01
Project Title: Functionalized, Nanoscale Coatings for Islet Encapsulation
Abstract: While clinical islet transplantation (CIT) has shown promise for the treatment of Type 1 diabetes, it is dampened by the impaired function and loss of islets following implantation. This loss is attributed to strong inflammatory and immunological response to the transplant, primarily due to cell surface inflammatory proteins and antigens. In this proposal, we seek to minimize detrimental host responses that lead to islet engraftment failure by encapsulating the islets in novel nanoscale biomaterial layers. By developing stable capsules on the order of 1000-fold smaller than standard practices via controlled covalent linking of individual polymers layers on the islet surface, void volumes are dramatically reduced and nutritional transport and glucose sensing is unaffected. Nanoscale layers not only serve as a means to immunocamouflage the implant, but also have tremendous potential to optimize the composition, structure, thickness, and function of these layers on the nanometer level. Once fabricated, these nanoscale layers serve as ideal platforms for the tethering of functional agents, proteins or markers capable of dynamically interacting at the implant-host interface. Therefore, the inert biomaterial layer can be converted to a bioactive surface capable of actively altering the localized implant environment. In this proposal, we seek to tether active immunomodulatory proteins/enzymes, anti-inflammatory agents, and/or engraftmentenhancing nanoparticles to the nanolayer surface. The design of effective strategies to build tailored nano-layers on the islet surface capable of expressing active proengraftment agents could significantly improve transplant efficacy and long-term stability. Public Health Relevance Statement: The public health implications of this research are that this approach may provide a means to dramatically improve current clinical islet transplantation results, by reducing or completely eliminating the need for immunosuppressive therapy and improving longterm implant function.
PI Name: Ben Z. Stanger, M.D., Ph.D.
Institution: University of Pennsylvania
Project Number: DP2 DK083111-01
Project Title: An In Vivo Approach to Cell-Based Therapy for Type 1 Diabetes
Abstract: For patients with type 1 diabetes mellitus (T1DM), the greatest prospect for reduced morbidity and insulin independence is the replacement of β-cells coupled with suppression of the underlying autoimmune process. Since the dramatic successes of islet transplantation in achieving this goal with donor islets, significant efforts have been directed at identifying and expanding alternate sources of β-cells. These efforts have been hampered by several challenges: adult β-cells are mainly derived by the replication of existing β-cells, non-β cells give rise to β-cells with low efficiency, and the β-cell phenotype is difficult to achieve or maintain in vitro. In tissues that maintain mass by replication of existing cells, certain forms of injury result in the emergence of a normally quiescent progenitor cell population (“facultative stem cells”). Previous studies indicate the presence of such a population in the adult pancreas, but findings have been inconsistent and the precursor population has been elusive. This proposal builds on convincing evidence that facultative stem cells reside within the pancreatic ducts and can give rise to large numbers of β-cells following obstruction of the pancreatic duct. This proposal seeks to identify the cells that exhibit this potential, and to develop practical methods for the efficient initiation of duct-to-islet conversion in vitro and in vivo. Specifically, our goal is to stimulate duct-to- β-cell reprogramming in rodents with established diabetes as a proof-of-principle. The proposed studies have the potential for a major impact on the treatment of T1DM by promoting β-cells neogenesis through the introduction of peptides or small molecules into pancreas. Public Health Relevance Statement: Type 1 diabetes is caused by the loss of β-cells, the insulin-producing cells of the pancreas. The goal of this proposal is to restore normal levels of insulin in diabetic patients by using an individual’s own pancreatic cells as a source for new β-cells.
PI Name: Bridget K. Wagner, Ph.D.
Institution: Massachusetts Institute of Technology
Project Number: DP2 DK083048-01
Project Title: Small-Molecule Approaches to Restore Glycemic Control in Type 1 Diabetes
Abstract: Beta-cell death, and the concomitant deficiency in insulin secretion, is a key feature of type 1 diabetes. Loss of glycemic control in type 1 diabetes represents the most direct target for clinical intervention. For decades, the standard of care for type 1 diabetes has been insulin injection. Current approaches to develop new treatments have prioritized islet transplantation and directed stem-cell differentiation, while many technological advances have focused on glucose detection and insulin delivery methods. However, a chemical intervention capable of restoring glycemic control would have enormous impact clinically, by enabling an in vivo pancreatic effect while avoiding the need for immunosuppression. In this Type 1 Diabetes Pathfinder proposal, I describe a chemical biology approach to 1) develop a suite of cell-based assays for high-throughput screening to identify small molecules that prevent cytokine-induced beta-cell death, and 2) use a novel high-throughput metabolic-profiling technology to assess nutrient dependence on pancreatic cell viability and function. Compounds identified in the first approach would serve as candidates for improvement of beta-cell function in cell culture and, ultimately, for therapeutic follow-up. The second approach will enable a metabolic networkdependent dissection of the differences between various pancreatic endocrine and exocrine cell types, and how nutrient metabolism affects beta-cell viability and function. The success of this project has the potential for enormous clinical impact on type 1 diabetes, by paving the way toward the development of novel drugs to prevent beta-cell death and thus restore glycemic control in patients; this project also represents one of the first large-scale efforts to screen for compounds with an impact on beta-cell biology. Public Health Relevance Statement: Type 1 diabetes results from a loss of insulin production by the pancreas; a chemical therapy that increases this function of the pancreas would make patients with type 1 diabetes less dependent on insulin injection for survival. This proposal aims to identify candidate compounds that prevent the pancreatic cell death that occurs in type 1 diabetes, and to understand what role cellular metabolism plays in pancreatic function. Ultimately, such chemicals could have the potential to replace insulin injection as the standard of care for this disease.
PI Name: Xingxing Zang, Ph.D.
Institution: Albert Einstein College of Medicine of Yeshiva University
Project Number: DP2 DK083076-01
Project Title: New T Cell Coinhibitory Pathway and Type 1 Diabetes
Abstract: T lymphocytes are central mediators of autoimmune responses that lead to type 1 diabetes. Optimal activation, proliferation, and differentiation to effector function of T cells require a simultaneous occurrence of two signals: antigen specific signals via T cell antigen receptors, and additional costimulatory signals (costimulation) generated primarily by the interaction between the B7 and CD28 families. The intense effort towards understanding T cell costimulation of B7-1, B7-2/CD28, CTLA-4 pathway over the past decade has shaped much of our understanding regarding the immune system and immune-related diseases such as type 1 diabetes. We have discovered the newest member of the B7 family, B7x, which is capable of inhibiting T cell function in vitro (coinhibition). However, the role of B7x in diabetes is unknown. Interestingly, we have recently found that, unlike B7-1 and B7-2, both human and mouse B7x genes are located in insulindependent diabetes loci and are expressed in pancreatic islets. Moreover, we have found that transgenic mice over-expressing B7x in pancreatic β cells are resistant to CD4 T cell mediated type 1 diabetes. Based on the preliminary data, we have hypothesized that B7x represents a novel T cell coinhibitory pathway that attenuates effector T cell function in the pancreas. We have generated some important tools that provide us with unique opportunities to address our hypothesis. The overall goal of this project is to provide fundamental insights into the role of the B7x pathway in type 1 diabetes. Public Health Relevance Statement: The outcome of this research may not only advance our understanding of the pathogenic processes underlying type 1 diabetes and its complications but also lead to a rational approach for clinical therapeutic intervention.