Microphysiological Systems for Modeling Autoimmunity in Type 1 Diabetes
Contact PI: Ben Stanger, MD, PhD, University of Pennsylvania (UG3 DK122644)
Dan Huh, PhD, University of Pennsylvania, Investigator
James Riley, PhD, University of Pennsylvania, Investigator
Paul Gadue, PhD, Children’s Hospital of Philadelphia, Investigator
Ali Naji, MD, University of Pennsylvania, Co-Investigator
Wenli Yang, PhD, University of Pennsylvania, Co-Investigator
Start Date: August 1, 2019
Abstract
This proposal leverages our group’s complementary expertise in tissue-on-a-chip technology, immunology, pluripotent cell derivation and differentiation, and islet biology to create robust systems containing human islet cells, immune cells, and other features to recapitulate the process of islet autoimmunity in type I diabetes (T1D). The UG3 phase of this proposal will improve upon already-robust microdevices and develop new cell lines and assays that will enable studies of autoimmunity in an isogenic setting. The UH3 phase of this proposal will exploit these tools and platforms to develop isogenic models that can be used to study immune-islet interactions. The focus of the UH3 phase will be to investigate the determinants of islet infiltration and killing, and to determine the effects of mutations in T1D-associated genes on this process. In addition, these in vitro systems will be used to pilot the use of cellular therapies to interrupt the autoimmune attack of islets. The specific aims of the UG3 phase are: Aim 1: To expand the biomimetic platform Aim 2: To develop models of T cell-mediated autoimmunity Aim 3: To establish new iPSC lines and novel reporters of b cell stress and death The specific aims of the UH3 phase are: Aim 1: To develop isogenic models of autoimmune T1D Aim 2: To identify determinants of islet infiltration and immune killing Aim 3: To perform genetic studies of autoimmunity in T1D
Meet the Grant Team
Investigators |
Ben Stanger, MD, PhDInvestigator |
Dan Huh, PhDInvestigator |
James Riley, PhDInvestigator |
Paul Gadue, PhDInvestigator |
Co-Investigators |
Ali Naji, PhDInvestigator |
Wenli Yang, PhDCo-Investigator |
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Publications
- Generation of non-human primate CAR Tregs using artificial antigen-presenting cells, simian tropic lentiviral vectors, and antigen-specific restimulation
- Geometric engineering of organoid culture for enhanced organogenesis in a dish
- Genome Engineering Human ESCs or iPSCs with Cytosine and Adenine Base Editors
- Trafficking and persistence of alloantigen-specific chimeric antigen receptor regulatory T cells in Cynomolgus macaque
- Cell type determination for cardiac differentiation occurs soon after seeding of human-induced pluripotent stem cells
- Genetic engineering of T cells for immunotherapy
- Genome Editing Human Pluripotent Stem Cells to Model β-Cell Disease and Unmask Novel Genetic Modifiers
- Ultrasensitive antigen density discrimination by synNotch
- Generation of a double insulin and somatostatin reporter line, SCSe001-A-3, for the advancement of stem cell-derived pancreatic islets
- Characterization of CAR T cell expansion and cytotoxic potential during Ex Vivo manufacturing using image-based cytometry
- iPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human islets