During the last decade, a specific class of RNA cis-elements that are rich in adenylate- and uridynalate bases (AU-rich elements, AREs) have arisen as strong instability determinants and translational modulators with important implications in pathophysiology. We aim to identify the functional properties of specific ARE binding proteins and associated signalling cascades of significance to disease. For example, HuR (HuA, Elavl1) and hnRNPD/AUF1 as well as numerous MAPK/SAPK signals target ARE-containing mRNAs-encoding early response genes, cytokines, growth factors and cell cycle regulators-that have been associated with numerous pathological conditions We hypothesize that these proteins play pleiotropic roles in the organization of translational regulation and the turnover of ARE-containing messages, in an obligatory or inducible manner. We explore these mechanisms using numerous molecular, cellular and functional genomics platforms.

Animal models of post-transcriptional dysfunction

Post-transcriptional regulators are widely expressed making their tissue restricted analysis difficult. Conditional systems of gene permutation in the mouse provide an outstanding tool to overcome this obstacle and analyse tissue specific pathological post-transcriptional networks in vivo. Furthermore they provide an invaluable tool for the assessment of gene function in disease susceptibility or resistance. We employ these platforms to analyse the functional role of specific RNA binding proteins in physiological cellular processes as well as in systemic and organ specific pathology (autoimmunity, inflammation, neurodegeneration and cancer).

Identification and definition of novel post-transcriptional modules

Current concepts favour that mRNA processing may proceed in clusters that are defined by "cognitive" mRNA:RBP interactions. It is also plausible that a specific mRNA cluster may direct a defined -physiological or pathological- cellular phenotype. We aim to identify novel RBP:RNA associations and assess their response to immune signals through their interaction with clusters of messages in selected cell types in transgenic systems of RBP or signalling permutations, through the integration of transgenic technologies to genomic, ribonomic and proteomic platforms.