Glucocorticoid receptor in health and disease

Abstract

Glucocorticoid hormones are essential for life, have a vital place in the treatment of inflammatory and autoimmune diseases and are increasingly implicated in the pathogenesis of a number of common disorders. Their action is mediated by an intracellular receptor protein, the glucocorticoid receptor (GR), functioning as a ligand-inducible transcription factor. Multiple synthetic glucocorticoids are used as potent antiinflammatory and immuno suppressive agents, but their therapeutic usefulness is limited by a wide range and severity of side-effects. One of the most important pharmaceutical goals has been to design steroidal and non-steroidal GR ligands with profound therapeutic efficacy and reduced unwanted effects. The therapeutic benefit of glucocorticoid agonists is frequently compromised by resistance to glucocorticoids, which may depend on: access of the hormones to target cells, steroid metabolism, expression level and isoform composition of the GR protein, mutations and polymorphisms in the GR gene and association of the receptor with chaperone proteins. The major breakthrough into the critical role of glucocorticoid signaling in the maintenance of homeostasis and pathogenesis of diseases, as well as into the molecular mechanisms underlying the therapeutic usefulness of antiinflammatory drugs acting through the GR is expected to result from the current progress in large-scale gene expression profiling technologies and computational biology.Glukokortikoidni hormoni su neophodni za održavanje homeostaze, imaju ključnu ulogu u terapiji inflamatornih i autoimunih poremećaja i učestvuju u pato - genezi mnogih bolesti. Ovi hormoni deluju posredstvom unutarćelijskog receptornog proteina, glukokortikoidnog receptora, koji funkcioniše kao inducibilan transkripcioni faktor aktiviran ligandom. Mnogi sintetski glukokortikoidi koriste se kao efikasni antiinflamatorni i imunosupresivni agensi, ali je njihov terapeutski učinak ograničen širokim spektrom i intenzitetom sporednih efekata. Jedan od najvažnijih ciljeva farmaceutske industrije jeste sinteza steroidnih i nesteroidnih liganada GR-a sa izraženom terapeutskom efikasnošću i redukovanim neželjenim efektima. Terapeutski učinak glukokortikoidnih agonista često je umanjen zbog rezistencije na glukokortikoide koja zavisi od: dostupnosti ciljnih ćelija hormonima, metabolizma steroida, nivoa ekspresije i izoformskog sastava GR, mutacija i polimorfizama u genu za receptor i interakcije receptora sa šaperonima. Očekuje se da veliki prodor u upoznavanju ključne uloge glukokortikoidnih hormona u održavanju homeostaze i patogenezi bolesti, kao i u rasvetljavanju molekularnih mehanizama terapeutskih efekata antiinflamatornih lekova koji deluju posredstvom GR rezultira iz napretka savremenih tehnologija za globalno izučavanje ekspresije gena i bioinformatike.Projekat ministarstva br. 14300