Modeling diabetes using an integrated plate system

使用集成板系统模拟糖尿病

• 批准号: 10229625
• 负责人: MOO-YEAL LEE
• 金额: $ 157.8万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 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/10229625
• 关键词: 3-Dimensional; 3D Print; Adhesives; Adsorption; Agonist; Amino Acids; Animal Model; Animals; Basic Science; Beta Cell; Biological; Biomimetics; Blood Glucose; Body Weight decreased; Caloric Restriction; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Communication; Culture Media; Development; Diabetes Mellitus; Digestion; Disease model; Disease remission; Eating; Engineering; Exercise; Extracellular Matrix; Face; Fatty Liver; Functional disorder; GCG gene; Gastrointestinal Hormones; Gastrointestinal tract structure; Glucose; Goals; Growth; Homeostasis; Hormone Responsive; Hormone secretion; Hormones; Human; Hydrogels; Hyperglycemia; Hyperplasia; Immune system; Impairment; In Vitro; Individual; Inflammation; Injections; Insulin; Insulin Resistance; Intestines; Islets of Langerhans; Life Style; Lipids; Liquid substance; Liver; Liver Fibrosis; Liver diseases; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metformin; Modeling; Molds; Nervous system structure; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Organ; Organ Model; Organoids; Pancreas; Patients; Perfusion; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Physiology; Plastics; Play; Pluripotent Stem Cells; Polymers; Prevalence; Printing; Pump; Reporter; Reproducibility; Role; Scientist; Silicon; Sulfonylurea Compounds; System; Technology; Testing; Therapeutic; Thiazolidinediones; Time; Tissue Microarray; Tissues; Tube; Vascular System; World Health Organization; bariatric surgery; base; bioprinting; body system; chemical property; design; drug discovery; exenatide; exosome; glucagon-like peptide 1; glucose uptake; glycemic control; high throughput screening; human model; human pluripotent stem cell; improved; in vitro Model; in vivo; incretin hormone; inhibitor/antagonist; insulin secretion; insulin signaling; liver inflammation; microphysiology system; novel therapeutics; nutrient absorption; physical property; preclinical evaluation; prototype; response; rosiglitazone; screening; technology validation

Summary: Modeling Diabetes in an Integrated Plate System The control of nutrient homeostasis involves the cross talk between multiple organ systems including the gastrointestinal tract, liver, endocrine pancreas, and nervous system, among others. Eating, digestion and nutrient absorption trigger a number of downstream effects on the liver and pancreas that are mediated by nutrients and GI hormones. Type 2 diabetes (T2D) is a metabolic disease that involves all of these organ systems. The most effective cure for T2D is gastric bypass surgery, which is invasive and has complications, but results in improved beta cell function and reversal of insulin resistance in the liver. It is not known why surgery is curative, however the changes in GI hormones that accompany this reversal of T2D are believed to contribute. Current efforts to study the interplay between liver, pancreas and the GI tract have depended on animal models, which often do not recapitulate human physiology. Moreover due to the inter-organ effects of systemic factors like hormones and nutrients, it is challenging to separate direct vs indirect effects on organ systems in vivo. This proposal aims to develop a tractable, high throughput fluidic system containing human pluripotent stem cell (PSC)-derived liver, pancreas and intestine to study inter-organ crosstalk, to identify mechanisms involved in reversal of T2D, and to develop a high throughput-screening platform for basic research and therapeutic screening purposes. Aim 1: Develop integrated plate systems that can support organoid function and communication. Manufacture and deliver 36PillarPlate system (UG3) 384PillarPlate (UH3) systems. Aim 2: Synthesize tunable hydrogels for robust and reproducible organoid growth and function. Identify biomimetic hydrogels that support the short-term growth of liver, intestinal and pancreatic tissues (UG3) and support organoid function and growth for 4 weeks (UH3). Aim 3: Establish liver, intestine, and pancreas organoids in the integrated plate system. Incorporate and test individual organoid systems for function on 36PillarPlate (UG3) 384-well micropillar platform (UH3). Test for organ function and crosstalk for up to 4 weeks. Aim 4: Validate the integrated plate system with known therapeutics for T2D (UH3 only).

总结：在集成板系统中建模糖尿病 营养平衡的控制涉及多个器官系统之间的相互作用，包括 胃肠道、肝脏、内分泌胰腺和神经系统等。进食、消化和 营养吸收引发了许多对肝脏和胰腺的下游影响，这些影响是由 营养素和胃肠道激素。2型糖尿病（T2D）是一种代谢性疾病，涉及所有这些器官 系统. T2D最有效的治疗方法是胃旁路手术，这是侵入性的，有并发症， 但导致改善的β细胞功能和逆转肝脏中的胰岛素抵抗。原因不明 手术是治愈性的，然而，伴随T2D逆转的GI激素变化被认为 贡献.目前研究肝脏、胰腺和胃肠道之间相互作用的努力依赖于 动物模型，通常不能概括人类生理学。此外，由于器官间的影响， 系统因素如激素和营养素，很难区分对器官的直接与间接影响， 体内系统。该建议旨在开发一种易于处理的、高通量的包含人的流体系统。 多能干细胞（PSC）衍生的肝脏，胰腺和肠研究器官间串扰，以确定 T2D逆转机制，并开发一个高通量筛选平台， 研究和治疗筛选目的。 目标1：开发可以支持类器官功能和通信的集成板系统。 制造和交付36柱板系统（UG3）和384柱板系统（UH3）。 目的2：合成可调水凝胶，用于稳健和可再现的类器官生长和功能。识别 支持肝脏、肠和胰腺组织短期生长的仿生水凝胶（UG3）， 支持类器官功能和生长4周（UH3）。 目的3：在集成板系统中建立肝、肠和胰腺类器官。 在36PillarPlate（UG3）384孔微柱上整合并测试单个类器官系统的功能 平台（UH3）。器官功能和串扰测试长达4周。 目的4：使用已知的T2D治疗方法（仅UH3）植入集成接骨板系统。