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: 9669312
• 负责人: D. Lansing Taylor
• 金额: $ 117.26万
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9669312
• 关键词: 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; human model; improved; induced pluripotent stem cell; insulin secretion; knock-down; male; microphysiology system; migration; potential biomarker; prevent; 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).

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 超过 3000 万美国人患有糖尿病，约占成年人口的 9.4%，另有 84 人患有糖尿病。 100 亿美国成年人患有糖尿病前期，每年造成的经济损失达 3220 亿美元。 所有形式糖尿病的根本原因是胰岛素分泌相对于代谢需求不足。 虽然 1 型糖尿病 (T1D) 中由于自身免疫破坏而导致 β 细胞绝对损失，但 2 型糖尿病 (T2D) 的发病机制更加异质，之前的胰岛素抵抗是 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 肌肉的胰岛素抵抗和代谢后果因组织而异，更重要的是， 此外，来自人类和模式生物研究的证据表明。 证明了器官串扰的重要性，包括肌因子、脂肪因子、肝因子和 来自炎症细胞的细胞因子，以及病理生理学中 miRNA 的外泌体转移 人类和模式生物生理学之间的种间差异限制了糖尿病的可翻译性。 许多研究结果（例如来自转基因小鼠的研究），例如来自β细胞的研究结果，所有这些都使其成为可能。 有必要设计体外系统来研究允许器官串扰询问的人体生理学。 了解人体微生理学系统 (MPS) 中 T2D 的病理生理学将有助于理解 疾病的生物标志物进展和治疗制定可以预防、减轻或 我们的建议集中于以下两个方面：扭转与糖尿病相关的发病率并改善患者的治疗结果。 关键器官：肝和胰岛，我们将首先演示相关的生理学和功能。 血管化肝腺泡 MPS (vLAMPS) 和血管化胰岛 MPS 的病理生理学 (vPANIS) 使用原代人类细胞/组织（目标 1） MPS 疾病模型的全部功能将利用患者- 源自器官中所有关键细胞的成体 iPSC，并包括关键细胞的实时荧光生物传感器 我们的提案有一个战略计划： 优化从 UG3 期的原代人类细胞到后期阶段的 iPSC 衍生细胞的迁移 UH3阶段，包括iPSC领域相关进展的协作整合（目标2和4）。 人类初级、基于细胞的 MPS 的初始使用将定义每个 MPS 中的最佳正常和疾病指标 模型开始疾病的研究并作为测试生理功能的功能参考 我们将在功能上和物理上将 vLAMPS 连接到 iPSC 衍生模型。 vPANIS 检验来自胰岛素抵抗肝脏的因素可以增强 β 细胞功能障碍的假设 我们将使用我们的微生理学数据库作为高血糖和高胰岛素血症的背景。 一个用于共享数据、协议、试剂、vLAMPS 和 vPANIS 模型和结果的平台（目标 5）。