Role of the induction of smICER and ICER in the heart

• Applicant: Professor Dr. Frank Ulrich Müller
• Subject Area: Pharmacology
• Term: from 2010 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 174776967

Heart failure is characterized by impaired myocardial contraction and is associated with a poor prognosis. Characteristic morphological and functional alterations (e.g. hypertrophy, decreased contractility) are summarized by the term Cardiac Remodeling. The molecular mechanisms underlying remodeling-associated changes of cardiac gene regulation are not fully understood. A chronic stimulation of the cAMP-dependent signal transduction pathway by elevated plasma catecholamines is regarded as a fundamental pathogenetic factor of cardiac remodeling and heart failure. The transcription factor cAMP-responsive element modulator (CREM) binds to the cAMP-responsive element (CRE) located in the promoters of various eukaryotic genes and is expressed in multiple splice variants. CREM proteins contribute to the cAMP dependent gene regulation e.g. involved in the development of a beta-adrenoceptor mediated cardiac dysfunction or of atrial fibrillation, the control of apoptosis and cell proliferation, spermiogenesis and memory function. Inducible CREM isoforms, so called ICER proteins (Inducible cAMP Early Repressors), inhibit the binding of related factors to the CRE and the thereby mediated transcriptional activation. The transcription of ICER mRNAs is controlled by an intronic CRE-controlled and cAMP inducible promoter within the Crem gene. Our group has identified another cAMP/CRE-controlled intronic Crem promoter regulating the induction of so-called smICER transcripts and resultant CREM repressors. We observed a tissue-specific induction of smICER and ICER transcripts. In our project we study the functional role of ICER/smICER induction in the catecholamine-induced cardiac remodeling using specific genetic mouse models. In detail we aim to identify functionally and possibly therapeutically relevant target genes and to characterize possible differences between ICER and smICER isoforms regarding their specific roles in cardiac remodeling, as well as in regard to regulated genes and binding partners. This should lead to a better understanding of mechanisms underlying the pathogenesis of heart failure and cardiac remodeling.

• DFG Programme: Research Grants