Microphysiological systems for modeling autoimmunity in type 1 diabetes

总结 该提案利用了我们小组在组织芯片技术、免疫学、 多能细胞衍生和分化以及胰岛生物学，以创建含有人胰岛的稳健系统。 细胞、免疫细胞和其他特征来概括I型糖尿病（T1 D）中胰岛自身免疫的过程。 该提案的UG 3阶段将改进已经强大的微型器件，并开发新的细胞系， 这将使得能够在等基因环境中研究自身免疫的测定。该提案的UH 3阶段将利用 这些工具和平台开发可用于研究免疫-胰岛相互作用的同基因模型。的 UH 3阶段的重点将是研究胰岛浸润和杀伤的决定因素，并确定 T1 D相关基因突变对这一过程的影响。此外，这些体外系统将用于 试验使用细胞疗法来中断胰岛的自身免疫攻击。 UG 3阶段的具体目标是： 目标1：拓展仿生平台 目的2：建立T细胞介导的自身免疫模型 目的3：建立新的iPSC细胞系和新的B细胞应激和死亡报告基因 UH 3阶段的具体目标是： 目的1：建立自身免疫性T1 D的同基因模型 目的2：确定胰岛浸润和免疫杀伤的决定因素 目的3：进行T1 D自身免疫的遗传学研究

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