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Brinkmann, Kay (2003): Entwicklung und Anwendung eines Expressionsklonierungssystems in primären Kardiomyozyten - Identifizierung von Translin als neuem Target der Herzinsuffizienz. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Development of an expression cloning system in primary cardiomyocytes - Validation of Translin as a new target for heart failure Congestive heart failure continues to represent a life threatening disease with unmet medical need. Functional impairment of the insufficient heart is reflected in altered geometry of the left ventricle. On the cellular level, cardiac myocytes respond to the increased biomechanical stress by different processes including sarcomeric remodelling and changes in cell shape. In order to identify new regulator genes for sarcomeric rearrangement, we developed an expression cloning system in primary cardiomyocytes. A normalized human heart library was integrated in an inducible adenoviral vector system. After transduction of cardiomyocytes and induction of the transgenes, cells were analyzed for morphological changes reflecting the hypertrophic process. A new system based on laser scanning cytometry was developed as read out. We managed to screen hundreds of cDNAs leading to the discovery of the new target protein Translin. Its overexpression caused the hypertrophic elongation of cardiomyocytes in vitro and could be involved in the pathologic regulation of posttranscriptional RNA processes. These data correlated with the upregulation of Translin in the diseased state of the human heart in vivo. In conclusion, this cell based screen led to the functional characterization of a novel regulator of heart disease providing a basis for the development of innovative drugs for the causative treatment of the insufficient human heart.