IMIM - Institut Hospital del Mar d'Investigacions Mèdiques

Signalling and gene expression in the immune system José Aramburu

 It's a UPF's Department of experimental and health sciences group. Summary of research in our group is:

Gene expression is the final result of complex signaling networks that communicate environmental changes to the nucleus of the cell. Once the sequencing of the human genome has been completed, a growing area of investigation is now concentrated in studying specificity, timing, and regulation of gene expression. The activity of a given transcription factor is the final step of a signal transduction process because it selectively influences chromatin areas to favor specific expression of its target genes.

Research in our group focuses on NFAT5, a recently discovered transcription factor that shares structural and functional characteristics with members of the NF-kappaB and NFAT families of proteins, key regulators of immune responses. NFAT5 is expressed and activated when cells are exposed to different stimuli like hypertonicity, antigen receptor-induced activation of T lymphocytes and alpha6/beta4 integrin signaling. Despite their differences, these stimuli affect cellular growth/size and have a major impact on cell communication and proliferation, influencing human diseases such as hypertension, diabetes, inflammation, autoimmunity and cancer.

The immune system is built from progenitor cells that differentiate and proliferate to specify the entire immune repertoire of an individual. In addition to that, antigen-driven activation of immune responses induces multiple differentiation and proliferation processes that further expands the immune repertoire towards specific effector’s phenotypes. On the other hand, immune responses represent a highly convenient - as well as relevant - model to understand transcriptional regulation. Most kinds of human and mouse immune cells are easily available and furthermore, multiple immune responses can be extensively analyzed ex vivo (i.e.: mixed lymphocyte reaction and exposure of peritoneal macrophages to different bacterial antigens). More important, the immune system is a network responsible for the appearance or clearance of multiple human diseases processes like autoimmunity, infection, graft’s rejection and cancer, providing a translation between basic research and potential clinical applications.

Understanding the relative contribution of NFAT5 versus other Rel (NF-kappaB and NFAT) proteins during immune responses, and also in other systems, is particularly relevant given that NFAT5 is activated by stimuli that both do (stimulation through the T lymphocyte receptor) and do not (hypertonicity) elicit the activation of NF-kappaB or conventional NFAT proteins. Moreover, the mechanism of activation of NFAT5 indicates that the analysis of its regulation and function could provide clues for manipulating immune responses and treating multiple diseases.

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