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: 10216387
• 负责人: D. Lansing Taylor
• 金额: $ 213.32万
• 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/10216387
• 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).

以肝脏和胰岛为起点的2型糖尿病人类微生理系统疾病模型 超过3000万美国人患有糖尿病，约占成年人口的9.4%。新增84个 在美国，有1000万成年人患有糖尿病前期，每年的经济损失达3220亿美元。的 所有形式的糖尿病的根本原因是相对于代谢需要的胰岛素分泌不足。 虽然由于自身免疫性破坏，1型糖尿病（T1 D）中的β细胞绝对丢失， 2型糖尿病（T2 D）的发病机制更加异质， 存在于许多组织中，主要是肝脏、胰岛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变化，更重要的是， 在人群中差异很大。此外，来自人类和模式生物研究的证据 证明了器官串扰的重要性，包括肌因子、脂肪因子、肝因子和 炎症细胞的细胞因子，以及miRNA的外泌体转移在炎症的病理生理学中的作用。 糖尿病人类和模式生物生理学之间的种间差异限制了 许多发现（如转基因小鼠研究），如β细胞研究。所有这些都使它 有必要设计体外系统来研究人体生理学，允许器官串扰询问。 了解T2 D在人体微生理学系统（MPS）中的病理生理学将有助于了解T2 D在人体微生理学系统中的作用。 疾病的进展，确定生物标志物和开发治疗策略，可以预防，减轻或 逆转与糖尿病相关的发病率并改善患者的预后。我们的建议集中在两个方面， 关键器官：肝脏和胰岛。我们将首先展示相关的生理学， 血管化肝腺泡MPS（vLAMPS）和血管化胰岛MPS的病理生理学 使用原代人细胞/组织（Aim 1）的vPANIS。MPS疾病模型的全部功能将利用患者- 衍生的，成年iPSC的器官中的所有关键细胞，并包括实时荧光生物传感器的关键 生理参数和所选基因的条件性敲除。我们的提案有一个战略计划， 优化从UG 3期的原代人细胞到iPSC衍生细胞的迁移， UH 3阶段，包括协作整合iPSC领域的相关进展（目标2和4）。的 最初使用人类原发性、基于细胞的MPS将定义每个MPS中的最佳正常和疾病度量 模型开始疾病的研究，并作为功能参考，以测试生理 iPSC衍生模型的相关性。我们将在功能上和物理上将vLAMPS耦合到 vPANIS检验来自胰岛素抵抗肝脏的因子可以增强β细胞功能障碍的假设， 高血糖症和高胰岛素血症的背景（目的3和4）。我们将使用我们的微生理学数据库， 共享数据、方案、试剂、vLAMPS和vPANIS模型和结果的平台（目标5）。