Modeling diabetes using an integrated plate system

使用集成板系统模拟糖尿病

• 批准号: 10474328
• 负责人: MOO-YEAL LEE
• 金额: $ 151.5万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474328
• 关键词: 3-Dimensional; 3D Print; Adhesives; Adsorption; Agonist; Amino Acids; Animal Model; Animals; Basic Science; Beta Cell; Biological Products; 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; 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; 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; Persons; 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; fatty liver disease; 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; 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).

摘要：在集成板系统中模拟糖尿病 营养稳态的控制涉及多个器官系统之间的串扰，包括 胃肠道、肝脏、内分泌胰腺和神经系统等。饮食、消化和 营养吸收会引发对肝脏和胰腺的一系列下游影响，这些影响是由 营养素和胃肠激素。 2 型糖尿病 (T2D) 是一种涉及所有这些器官的代谢性疾病 系统。 T2D 最有效的治疗方法是胃绕道手术，该手术是侵入性的并且有并发症， 但会改善β细胞功能并逆转肝脏中的胰岛素抵抗。目前尚不清楚原因 手术是治愈性的，但伴随 T2D 逆转的胃肠道激素的变化被认为 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 由于激素和营养素等全身因素，区分对器官的直接影响和间接影响具有挑战性 体内系统。该提案旨在开发一种易于处理、高通量的流体系统，包含人类 多能干细胞 (PSC) 来源的肝脏、胰腺和肠道来研究器官间串扰，以确定 逆转T2D的机制，并开发一个高通量筛选平台 研究和治疗筛选目的。 目标 1：开发能够支持类器官功能和通信的集成板系统。 制造和交付 36PillarPlate 系统 (UG3) 384PillarPlate (UH3) 系统。 目标 2：合成可调节的水凝胶，以实现稳健且可重复的类器官生长和功能。确认 支持肝脏、肠道和胰腺组织（UG3）短期生长的仿生水凝胶 支持类器官功能和生长 4 周 (UH3)。 目标 3：在集成板系统中建立肝脏、肠和胰腺类器官。 合并并测试单个类器官系统在 36PillarPlate (UG3) 384 孔微柱上的功能 平台（UH3）。长达 4 周的器官功能和串扰测试。 目标 4：使用已知的 T2D 疗法（仅限 UH3）验证集成板系统。

项目成果

Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids.

就肝脏、胰腺和胆道类器官的定义和命名建立共识。

• DOI: 10.1016/j.stem.2021.04.005
• 发表时间: 2021-05-06
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Ary Marsee;Floris J. M. Roos;M. Verstegen;H. Gehart;E. D. de Koning;F. Lemaigre;S. Forbes;Weng Chuan Peng;Meritxell Huch;T. Takebe;L. Vallier;H. Clevers;L. V. D. van der Laan;B. Spee
• 通讯作者: B. Spee