Enrico Schmidt, Merck KGaA, Novartis, Basel, Switzerland
Cellular behavior is tightly regulated by multiple pathways both in space and time. Modulation of all cellular mechanisms can therefore not only be achieved by targeted delivery of modulator to various subcellular compartments but also by different timing of the modulator. In classical drug discovery the effect of low molecular weight compounds is frequently tested in endpoint assay which limits the molecular mode of actions. When applied on imaging-based read-out, this strategy allows to un-couple cell-treatment from staining and imaging. This approach however does not cover the whole dynamic range or fails completely if no dynamic range can be defined or if the molecular read out cannot be visualized in an endpoint assay.
The clearance of apoptotic cells is a key process both during physiological and pathological processes like early development, cancer progression and resolution of inflammation. Engulfment of apoptotic cells is a highly dynamic process regulated by a complicated network of extra- and intracellular pathways. In order to identify modulators of this process with a broad molecular mode of action, dynamic live cell imaging is required. We have developed a fully automated imaging assay to measure uptake of apoptotic corpses using primary human cells in 1536 multi-well format that allows monitoring the complete dynamic range of the process and identify modulators with a broad molecular mode of action.