Islet on a Chip

芯片上的胰岛

• 批准号: 8813382
• 负责人: DOUGLAS A MELTON
• 金额: $ 684.42万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813382
• 关键词: Beds; Beta Cell; Biological Assay; Biology; Biomimetic Devices; Biomimetics; Blood Glucose; Cell Line; Cell Survival; Cell physiology; Cells; Complex; Development; Devices; Diabetes Mellitus; Disease; Disease model; Embryo; Endocrine; Engineering; Evaluation; Failure; Functional disorder; Generations; Geometry; Glucagon; Glucose; Goals; Hormones; Human; In Vitro; Incidence; Insulin; Islet Cell; Islets of Langerhans; Laboratories; Measures; Mechanics; Methods; Microfluidic Microchips; Microfluidics; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Organ; Organogenesis; Organoids; Pancreas; Pancreatic Polypeptide; Patients; Pharmaceutical Preparations; Physiology; Population; Preclinical Drug Evaluation; Production; Replacement Therapy; Reporter; Research; Role; Signal Transduction; Skeletal Muscle; Somatostatin; Source; Speed; Stem cells; Structure; Structure of beta Cell of islet; System; Technology; Testing; Therapeutic; Time; Tissue Engineering; Tissues; base; cell type; cost; design; diabetic; drug testing; ghrelin; human embryonic stem cell; improved; induced pluripotent stem cell; insulin sensitivity; interest; islet; islet stem cells; mortality; new technology; preclinical evaluation; progenitor; public health relevance; release of sequestered calcium ion into cytoplasm; research study; response; screening; self organization; stem; stem cell biology; technology development; therapeutic target; type I and type II diabetes

 DESCRIPTION: Mellitus results from failure pancreatic islets leading to an increase in morbidity and mortality. Mechanistic studies of this disease are hindered by low availability, high variabiliy and the cost of human islets. Our recent advances have led to the first successful method to generate mature, glucose sensing- insulin secreting b cells from human embryonic stem (ES) cells in vitro. This method, and its application using human iPS cells, provides a virtually unlimited supply of standardized human β cells. Moreover, as the β cells can be prepared from patient iPS cells, normal and diseased states can be analyzed. This advance provides a renewable source of b cells for cell replacement therapy for insulin dependent diabetics and the opportunity to perform rigorous disease modeling to identify therapeutic targets for all diabetics. Despite these advances, challenges remain. Robust, sensitive and routine technologies to assess β cell function are lacking. Further, it is unlikely that b cells by themselves will recapitulate the complex biology involved in islet function. As such, the proposed research aims to combine approaches in stem cell and islet biology with tissue engineering to design, build and test new technologies for generating human islets in vitro and assessing their function in microfluidic devices. Using reverse engineering principles we will design and build a bio-inspired microfluidic chip that supports the survival and function of cell clusters containing b cells. This "islet chip" design will enable rigorous and sensitive evaluation of β cell function that goes beyond current technologies. This chip will also provide a platform to evaluate human cadaveric islets by quantifying their functional variability. In parallel, we seek to generate whole islets i vitro using a combination of top-down and bottom-up tissue engineering approaches. Endocrine progenitors from human stem cells (ES and iPS) will be introduced to a chip designed to screen a combination of substrates, matrixes and mechanical forces to identify a niche that supports differentiation to islet-like structures with all endocrine cell types. The resulting stem cell-derved islets will be evaluated in our islet chip to describe the functional differences between these ES-islets, bcells alone and cadaveric islets. Finally, we will use these technologies for disease modeling and drug screening by generating healthy and diseased islets from iPS cells representing different disease states (healthy, type 1, type 2 diabetes, MODY) and evaluate the function and response of these islets to diabetes drugs. These studies will provide validated technologies that will increase our understanding of diabetes and speed development of new therapies.

 描述：糖尿病是由胰岛衰竭引起的，导致发病率和死亡率增加。这种疾病的机制研究因人类胰岛的可用性低、变异性高和成本高而受到阻碍。我们最近的进展导致第一个成功的方法在体外从人胚胎干 (ES) 细胞产生成熟的葡萄糖感应胰岛素分泌 b 细胞。这种方法及其在人类 iPS 细胞中的应用，提供了几乎无限量的标准化人类 β 细胞供应。此外，由于可以从患者 iPS 细胞中制备 β 细胞，因此可以分析正常和患病状态。这一进展为胰岛素依赖型糖尿病患者的细胞替代疗法提供了可再生的 b 细胞来源，并有机会进行严格的疾病建模以确定所有糖尿病患者的治疗靶点。 尽管取得了这些进展，挑战仍然存在。缺乏稳健、灵敏和常规的技术来评估 β 细胞功能。此外，b 细胞本身不太可能重现与胰岛功能有关的复杂生物学。因此，拟议的研究旨在将干细胞和胰岛生物学方法与组织工程相结合，设计、构建和测试用于体外生成人类胰岛并评估其在微流体装置中的功能的新技术。利用逆向工程原理，我们将设计和构建一种仿生微流控芯片，支持含有 b 细胞的细胞簇的存活和功能。这 “胰岛芯片”设计将能够对β细胞功能进行严格而灵敏的评估，这超出了现有技术。该芯片还将提供一个平台，通过量化人类尸体胰岛的功能变异性来评估其功能。与此同时，我们寻求结合自上而下和自下而上的组织工程方法在体外生成完整的胰岛。来自人类干细胞（ES 和 iPS）的内分泌祖细胞将被引入一种芯片，该芯片旨在筛选底物、基质和机械力的组合，以确定支持所有内分泌细胞类型分化为胰岛样结构的生态位。由此产生的干细胞来源的胰岛将在我们的胰岛芯片中进行评估，以描述这些 ES 胰岛、单独的 b 细胞和尸体胰岛之间的功能差异。最后，我们将利用这些技术进行疾病建模和药物筛选，从代表不同疾病状态（健康、1型、2型糖尿病、MODY）的iPS细胞生成健康和患病的胰岛，并评估这些胰岛的功能和对糖尿病药物的反应。这些研究将提供经过验证的技术，增加我们对糖尿病的了解并加速新疗法的开发。