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).