The design and characterisation of chemically stable and selective synthetic retinoids.

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Retinoid acid (RA) and its natural and synthetic derivatives, often called retinoids, control a wide range of cellular processes in chordates, including differentiation, proliferation, apoptosis and homeostasis, by regulating transcriptional control in the cell nucleus. Retinoids are high affinity ligands for a family of nuclear receptor proteins - retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Once bound to these receptors, dimerization allows the formation if activeve heterodimers (RAR/RXR) that are able to bind their target DNA sequences and initiate transcription. In order to reach the nucleus, the highly lipophilic retinoids are bound to a carrier protein, the Cellular Retinoic Acid Binding Protein (CRABPII). Intriguingly, CRABPII also binds to Cyclin D3, one of the key regulators of Cyclin Dependent Kinases (CDKs) that in turn regulate the cell cycles in all eukaryotic cells. The overall goal of this project is to develop an entire tool box of synthetic retinoids that are specific for each type of CRABP, and each member of the RAR family that can be used for application ranging from drug discovery to fluorescent probes in cell biology. The protein-ligand interaction will be characterized using a wide range of biochemical, biophysical and structural tools.