Microphysiological systems for modeling autoimmunity in type 1 diabetes

用于模拟 1 型糖尿病自身免疫的微生理系统

• 批准号: 10467045
• 负责人: PAUL J GADUE
• 金额: $ 112.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467045
• 关键词: Address; Affect; Allogenic; American; Animal Model; Antigen Presentation; Antigen-Antibody Complex; Autoimmune; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autopsy; B cell differentiation; B-Lymphocytes; Biological Models; Biology; Biomimetics; Blood Vessels; Cell Death; Cell Line; Cell Therapy; Cells; Cellular Assay; Cellular Stress; Derivation procedure; Development; Endothelial Cells; Engineering; Exocrine pancreas; Fibroblasts; Functional disorder; Future; Genes; Genetic study; Goals; Heterogeneity; Human; Immune; Immune system; Immunity; Immunology; In Vitro; Individual; Infiltration; Insulin; Insulin-Dependent Diabetes Mellitus; Interruption; Intervention; Investigation; Islet Cell; Islets of Langerhans; Knowledge; Lead; Leukocytes; Mediating; Methods; Modeling; Molecular; Mutation; Organoids; Pancreas; Pathogenesis; Patients; Phase; Phenotype; Population; Positioning Attribute; Process; Protocols documentation; Regulatory T-Lymphocyte; Reporter; Reproducibility; Research; Resources; Role; Series; Signal Transduction; Site; Source; Splenocyte; Structure of beta Cell of islet; System; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic; Time; Tissue Banks; Tissues; Transgenic Organisms; autoimmune pathogenesis; cell bank; cell killing; chimeric antigen receptor T cells; diabetes pathogenesis; endoplasmic reticulum stress; engineered T cells; experimental study; imaging system; improved; in vitro Model; induced pluripotent stem cell; innovation; insight; islet; islet autoimmunity; microdevice; microphysiology system; microsystems; novel; novel strategies; programmed cell death protein 1; programs; tool

SUMMARY 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

概括 该提案利用了我们团队在芯片组织技术、免疫学、 多能细胞衍生和分化，以及胰岛生物学，以创建包含人类胰岛的强大系统 细胞、免疫细胞和其他特征来概括 I 型糖尿病 (T1D) 中胰岛自身免疫的过程。 该提案的 UG3 阶段将改进已经强大的微型设备并开发新的细胞系和 能够在等基因环境中研究自身免疫的测定。该提案的 UH3 阶段将利用 这些工具和平台可用于开发可用于研究免疫胰岛相互作用的等基因模型。这 UH3阶段的重点将是研究胰岛渗透和杀灭的决定因素，并确定 T1D 相关基因突变对此过程的影响。此外，这些体外系统将用于 试点使用细胞疗法来中断胰岛的自身免疫攻击。 UG3阶段的具体目标是： 目标1：扩展仿生平台 目标 2：开发 T 细胞介导的自身免疫模型 目标 3：建立新的 iPSC 系和 B 细胞应激和死亡的新报告基因 UH3阶段的具体目标是： 目标 1：开发自身免疫性 T1D 的同基因模型 目标 2：确定胰岛浸润和免疫杀伤的决定因素 目标 3：进行 1 型糖尿病自身免疫的遗传学研究