To bring such a tool to the development of type 1 diabetes therapeutics, we have developed a physiologically based mathematical model, the Type 1 Diabetes PhysioLab® platform, which reproduces type 1 diabetes pathogenesis in a NOD mouse from birth to diabetes onset, with extensive representation of the pancreas, the pancreatic lymph nodes (PLN) and the dynamic interactions and activities of multiple cell populations. BMS-777607 The Type 1 Diabetes PhysioLab platform employs a ‘top-down’ modelling

approach to represent type 1 diabetes pathogenesis in the NOD mouse. In brief, this requires identification of the whole-animal or system-level behaviours which the model must reproduce (i.e. the ‘top’ level of modelling), as well as the biological components and mechanisms whose integrated and dynamic function generates these behaviours. Type 1 diabetes in the laboratory NOD mice is characterized typically by several months of normal blood glucose (normoglycaemia), before the onset of clinical symptoms, defined most commonly by elevated blood glucose (hyperglycaemia). Blood glucose levels are regulated by insulin release from beta cells (β cells) located in the pancreatic islets. Immune cell infiltration of the islets is initially detectable by 3–4 AZD1208 chemical structure weeks of age

and worsens progressively with time, where disease progression is correlated with a diminution in β cells. Further, autoreactive T cell priming and expansion have been documented in the draining pancreatic lymph nodes (PLN) [2]. Based on Liothyronine Sodium this understanding of type 1 diabetes, the Type 1 Diabetes PhysioLab platform explicitly represents islet β cells, autoimmune cells and mechanisms of activation and effector function, leading to loss

of islet β cells and impaired glucose control (further details provided below). Notably, this top-down modelling approach requires explicit representation of the system-level behaviours of interest and allows variability in the parameterization of the underlying biology. This differs from a ‘bottom-up’ approach, which gathers and integrates all available data at a fundamental level, often providing valuable insights into pathway interactions but rarely reproducing a system-level behaviour in the early modelling endeavours. Nevertheless, the top-down approach employed here has elements of bottom-up approaches as well, as it relies heavily on protein and expression data to characterize relationships among entities and to assign mathematical values to the representation (e.g. the rate of islet β cell insulin production). Physiologically based models such as the one described here are aimed at quantitatively integrating detailed biology across the system, and therefore comprise numerous state variables and parameters.