Characterization of SHOX2 and SHOX2 target genes in the pathogenesis of cardiac arrhythmias

• Applicant: Professorin Dr. Gudrun Rappold
• Subject Area: Human Genetics
• Term: from 2005 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5456078

Characterization of SHOX2 and SHOX2 target genes in the pathogenesis of cardiac arrhythmia. To elucidate molecular mechanisms underlying sinoatrial node development as well as pathophysiological processes of cardiac arrhythmias, we will address the critical role of the pacemaker-specific expressed gene SHOX2, its target genes and SHOX2 associated molecules. Using Shox2 as a molecular tool, we successfully established an embryonic stem cell based model system, which will be used to investigate novel molecular pathways regulating early pacemaker differentiation. Furthermore, we will analyze the functional relevance of recently identified SHOX2 mutations and a SHOX2 3 UTR (untranslated region) variant in patients with atrial fibrillation in detail. We will use cell culture based in vitro approaches, as well as Zebrafish as an in vivo model system. In addition, we will perform mutational screening of the SHOX2 gene in further patients with sinusnode dysfunction. To functionally characterize the SHOX2 coding variants and the 3 UTR variant, which creates novel microRNA binding sites, we will utilize induced pluripotent stem cells (iPSCs) to establish a patient-specific disease model.

• DFG Programme: Research Grants