<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Elucidating the role of SHOX2 in atrial fibrillation using a patient-derived human induced pluripotent stem cell model"^^ . "The sinoatrial node (SAN) is the primary pacemaker of the heart, where the pulse necessary for cardiac\r\ncontraction arises to be propagated to the cardiac chambers via the cardiac conduction system. The\r\ntranscription factor short stature homeobox 2 ( SHOX2 ) is essential for the development and function\r\nof the SAN, activating a transcriptional program for pacemaker development while suppressing\r\ndifferentiation towards working myocardium during cardiogenesis. Variants in the SHOX2 gene have\r\nbeen associated with atrial fibrillation (AF), the most common cardiac arrhythmia. However, the\r\npathomechanisms behind SHOX2 dependent AF and the SHOX2 regulatory genetic network have not\r\nbeen fully understood. Until now, the impact of Shox2 deficiency has only been investigated in mouse\r\nor zebrafish animal models. Therefore, the aim of this thesis was to gain new insights from a human\r\nbackground and to investigate whether data obtained via animal models can be transferred to a human\r\nmodel system. At the beginning of this work, two induced pluripotent stem cell (iPSC) lines from two\r\ndifferent patients with early onset AF were available, carrying a heterozygous single nucleotide variant\r\neither in the 3’UTR or in the coding region of SHOX2. A targeted correction of these variants had already\r\nbeen performed to generate isogenic control lines.\r\nFirst, I generated two homozygous SHOX2 KO iPSC lines from the available cell lines and validated them\r\nusing several methods. Furthermore, I established and adapted previously published differentiation\r\nprotocols to generate pacemaker and atrial cardiomyocytes (CMs) from iPSCs. To uncover variant specific changes in the two patient lines that contribute to the disease phenotype, I performed comparative profiling with their isogenic controls using gene expression analysis, single cell RNA\r\nsequencing and electrical phenotyping. Gene expression profiling of iPSC derived CMs confirmed several deregulated gene expression patterns known from animal models and uncovered additional dysregulation. Data from Single cell RNA sequencing revealed a possibly impaired differentiation\r\ncapability and disturbed mitochondrial function in the patient cells. In CMs of the 3’UTR variant patient\r\nline, changed action potential characteristics were discovered, which notably could be attributed to\r\ndifferential ion channel expression. M ost strikingly, upregulation of the Na+ channel SCN5A led to an\r\nincreased action potential upstroke velocity and amplitude, and upregulation of several K+ channels\r\ncaused a shortened repolarization time observed in the patient line. Thus, novel disease mechanisms\r\ncausing SHOX2 dependent AF as well as underlying molecular mechanisms and potential targets for\r\nadapted treatment strategies could be uncovered. Overall, the established human iPSC model and the\r\ndifferentiated cardiac cell types provide a valuable tool to further dissect the detailed molecular\r\nmechanisms of SHOX2 dependent AF in the future."^^ . "2025" . . . . . . . "Kristin"^^ . "Rädecke"^^ . "Kristin Rädecke"^^ . . . . . . "Elucidating the role of SHOX2 in atrial fibrillation using a patient-derived human induced pluripotent stem cell model (PDF)"^^ . . . "PhD Thesis_Kristin Rädecke_November 2023.pdf"^^ . . . "Elucidating the role of SHOX2 in atrial fibrillation using a patient-derived human induced pluripotent stem cell model (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Elucidating the role of SHOX2 in atrial fibrillation using a patient-derived human induced pluripotent stem cell model (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Elucidating the role of SHOX2 in atrial fibrillation using a patient-derived human induced pluripotent stem cell model (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Elucidating the role of SHOX2 in atrial fibrillation using a patient-derived human induced pluripotent stem cell model (Other)"^^ . . . . . . "small.jpg"^^ . . . "Elucidating the role of SHOX2 in atrial fibrillation using a patient-derived human induced pluripotent stem cell model (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #34630 \n\nElucidating the role of SHOX2 in atrial fibrillation using a patient-derived human induced pluripotent stem cell model\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .