The role of RORβ in human iPSC derived cardiomyocytes

by Setare Torkieh
Doctoral thesis
Date of Examination:2024-09-10
Date of issue:2024-09-10
Advisor:Prof. Dr. Gerd Hasenfuß
Referee:Prof. Dr. Gerd Hasenfuß
Referee:Prof. Dr. Laura Zelarayan-Behrend
Persistent Address: http://dx.doi.org/10.53846/goediss-10727

 

 

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Abstract

English

Every year systolic heart failure contributes immensely to the death tolls in industrialized nations. However, little is known about the molecular mechanisms underlying this devastating disease. Based on the RNA sequencing screens of biopsies from aortic stenosis patients, RORβ is thought to play a role in the heart’s transition to failure. As a transcription factor its observed increase in expression, specifically during the state of compensated hypertrophy, might hint towards a relevant downstream effect. This thesis aims to provide a greater insight and understanding of the complex gene regulatory networks and molecular mechanisms underlying adaptive and adverse remodeling processes of the heart during its progression to failure. Thereby the focus lies on the role of RORβ during the CMs early stress response in regards of changes in cell viability and resilience. The outcomes of this study support the hypothesis that RORβ acts as a stress moderating factor on a transcriptional and functional level. This study identified RORβ as a novel actor during the hearts transition to failure. Transcriptional and functional analysis of AAV-RORβ transduced CMs have revealed its predicted role in upholding homeostatic processes. By reducing the impact of oxidative stress on the cell’s viability, it might allow for a state of compensated hypertrophy to be maintained and postpone the progression to failure. Further understanding of these molecular processes is crucial for future pharmacological research and the translational opportunity this thesis might offer in the establishment of druggable targets for the treatment of HF.
Keywords: Heart Failure; Retinoid acid related orphan-receptor beta; Compensated Hypertophy
 
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