Human Microphysiology Systems Disease Model of Type 2 Diabetes Starting with Liver and pancreatic Islets

从肝和胰岛开始的 2 型糖尿病的人体微生理学系统疾病模型

• 批准号: 10228791
• 负责人: D. Lansing Taylor
• 金额: $ 28.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228791
• 关键词: 3-Dimensional; Adipose tissue; Adult; American; Animal Model; Autoimmune Process; Beta Cell; Biological Markers; Biological Models; Biosensor; Blood Vessels; Cell Line; Cells; Collaborations; Coupled; Coupling; Data; Databases; Development; Diabetes Mellitus; Disease; Disease Progression; Disease model; Endothelial Cells; Engineering; Fasting; Fluorescence; Functional disorder; Genes; Hepatocyte; Human; Hyperglycemia; In Vitro; Individual; Inflammatory; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Investigation; Islet Cell; Islets of Langerhans; Knock-in; Link; Liver; Metabolic; Methods; MicroRNAs; Microfluidics; Modeling; Morbidity - disease rate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Organ; Organ Model; Pathogenesis; Patient-Focused Outcomes; Patients; Phase; Physiological; Physiology; Population; Precision therapeutics; Prediabetes syndrome; Protocols documentation; Reagent; Role; Skeletal Muscle; Source; Strategic Planning; System; Technology; Testing; Therapeutic; Time; Tissues; Transgenic Mice; adipokines; base; biomarker development; biomarker discovery; clinically relevant; cytokine; data sharing; drug testing; economic cost; hepatic acinus structure; improved; induced pluripotent stem cell; insulin secretion; knock-down; male; microphysiology system; migration; potential biomarker; prevent; sharing platform; success

Human Microphysiology Systems Disease Model of Type 2 Diabetes Starting with Liver and Pancreatic Islets Over 30 million Americans have diabetes, constituting about 9.4% of the adult population. An additional 84 million adult Americans have pre-diabetes, both amounting to an economic cost of $322 billion annually. The underlying cause of all forms of diabetes is an inadequate insulin secretion relative to the metabolic needs. While there is an absolute loss of beta cells in type 1 diabetes (T1D) due to an autoimmune destruction, the pathogenesis of type 2 diabetes (T2D) is much more heterogeneous with preceding insulin resistance being present in many tissues, principally the liver, β-cells in pancreatic islets, white adipose tissue and skeletal muscle. The insulin resistance and the metabolic consequences vary between tissues and more importantly, vary enormously in the population. Furthermore, evidence from human and model organism studies has demonstrated the importance of organ crosstalk including the role of myokines, adipokines, hepatokines and cytokines from inflammatory cells, as well as the exosomal transfer of miRNA in the pathophysiology of diabetes. Interspecies differences between human and model organism physiology limits the translatability of many findings (e.g. from transgenic mouse studies), such as those from beta cells. All of these make it necessary to devise in vitro systems to study human physiology that allow organ crosstalk interrogation. Understanding the pathophysiology of T2D in a human microphysiology system (MPS) will help understand the progression of the disease, identify biomarkers and develop therapeutic strategies that can prevent, mitigate or reverse the morbidity associated with diabetes and improve patient outcomes. Our proposal focuses on two of the critical organs: liver and pancreatic islets. We will first demonstrate the relevant physiology and pathophysiology in the vascularized liver acinus MPS (vLAMPS) and the vascularized pancreatic islets MPS (vPANIS) using primary human cells/tissue (Aim 1). The full power of MPS disease models will utilize patient- derived, adult iPSCs of all of the key cells in the organs and include real-time fluorescent biosensors of key physiological parameters and conditional knock-downs of selected genes. Our proposal has a strategic plan to optimize the migration from primary human cells in the UG3 phase to iPSC-derived cells in the later stages of the UH3 phase, including collaborative integration of relevant progress in the iPSC field (Aim 2 and 4). The initial use of human primary, cell-based MPS’s will define the optimal normal and disease metrics in each MPS model to begin the investigation of the disease and to serve as a functional reference to test the physiological relevance of the iPSC-derived models. We will functionally and then physically couple the vLAMPS to the vPANIS to test the hypothesis that factors from the insulin resistant liver can potentiate beta cell dysfunction in the context of hyperglycemia and hyperinsulemia (Aims 3 and 4). We will use our microphysiology database as a platform for sharing data, protocols, reagents, the vLAMPS and vPANIS models and results (Aim 5).

人类微生物生理系统疾病2型糖尿病的模型从肝脏和胰岛开始 超过3000万美国人患有糖尿病，约占成年人口的9.4％。另外84 百万的成年美国人患有糖尿病前，每年的经济成本均为3220亿美元。这 各种形式的糖尿病的根本原因是相对于代谢需求的胰岛素分泌不足。 虽然由于自身免疫性破坏，但在1型糖尿病（T1D）中绝对丧失了β细胞，但 2型糖尿病（T2D）的发病机制更为异质，前面的胰岛素抵抗力为 存在于许多组织中，主要是肝脏，胰岛中的β细胞，白色脂肪组织和骨骼 肌肉。胰岛素抵抗和代谢后果在组织之间以及更重要的是 人口差异很大。此外，人类和模型生物研究的证据已经 展示了器官串扰的重要性，包括肌动物，脂肪因子，肝动力油和 来自炎症细胞的细胞因子，以及miRNA的外泌体转移 糖尿病。人与模型生理学之间的种间差异限制了转换性 许多发现（例如来自转基因小鼠研究），例如来自β细胞的发现。所有这些都做到了 设计体外系统以研究人类生理学的必要条件，以允许器官串扰询问。 了解人类微生物生理系统（MP）中T2D的病理生理学将有助于了解 疾病的进展，识别生物标志物并制定可以预防，减轻或 扭转与糖尿病相关的发病率并改善患者结局。我们的建议重点是 关键器官：肝脏和胰岛。我们将首先证明相关的生理学和 血管化肝脏腺泡MP（VLAMP）和血管化胰岛MPS中的病理生理 （VPANIS）使用原代人细胞/组织（AIM 1）。 MPS病模型的全部力量将利用患者 - 器官中所有关键细胞的成年IPSC衍生，包括KEY的实时荧光生物传感器 所选基因的生理参数和条件敲除。我们的建议有一个战略计划 优化在UG3期间从原代人细胞迁移到IPSC衍生细胞的后期阶段的迁移 UH3阶段，包括在IPSC领域中相关进度的协作集成（AIM 2和4）。这 最初使用基于细胞的MPS的人将定义每个MP的最佳正常和疾病指标 开始研究该疾病并作为测试生理的功能参考的模型 IPSC衍生模型的相关性。我们将在功能上，然后将VLAMP物理化为 VPANIS检验以下假设：胰岛素抗性肝脏的因素可以使Beta细胞功能障碍在 高血糖和高胰血症的背景（目标3和4）。我们将使用微生物生理学数据库作为 共享数据，协议，试剂，VLAMP和VPANIS模型和结果的平台（AIM 5）。