Research Report 2010 - MDC

Martin Liss*Brian Anderson**Technical AssistantsBeate GoldbrichMandy Terne**Melanie Manzke**Mirko Wehle**SecretariatSylvia Olbrich*part of the period reported** guest, part of the period reportedSchematic diagram of the sarcomere.Titin forms a continuous filamentsystem along the muscle fiberoverlapping in the M-band (titin C-terminus) and in the Z-disc (N-terminus).The titin kinase is foundnear the edge of the M-band region,while the elastic PEVK resides in theI-band. Titin interacts with a plethoraof sarcomeric proteins, such as T-cap and C-protein.compartments such as the chromosomes of drosophilaneuroblasts and the brush border of intestinal epithelialcells. Titin has been implicated in cytokinesisthrough localization to cleavage furrows and in chromosomecondensation through localization to mitoticchromosomes. Drosophila melanogaster deficient in thetitin homologue D-titin show chromosome abnormalitiesand aneuploidity.Our preliminary data indicate that titin is present in virtuallyevery cell-type tested. Nevertheless, our knockoutof titin’s M-band exon 1 and 2 does not show an obviousnon-muscle phenotype, such as a defect in implantationor in cell-migration. Accordingly, we have extendedthe analysis of our titin knockout animals to actin-filamentdependent functions (assembly of the brush border)and generated additional titin deficient animals toestablish the role of titin in non-muscle cells.Functional analysis of the Coxsackie-AdenovirusReceptorYu Shi, Chen Chen, Uta Wrackmeyer, Ulrike LisewskiCAR was cloned as a receptor used by adeno- and coxsackievirusto enter cells but its physiological role hasremained obscure. Detailed information on the expressionpattern such as upregulation surrounding myocardialinfarction and a critical role in embryonic development(lethality in mid-gestation of the CAR knockout)are well established, but no information on its role inthe adult heart has been available.We have generated both tissue culture and animalmodels to study CAR’s function in cardiac remodeling,inflammatory cardiomyopathy, and basic cellularprocesses such as endocytosis and cell-cell contact formation.Our preliminary data suggest a critical role of CAR in theconduction of electrical signals from the atria to thecardiac ventricle. The inducible heart-specific knockoutof CAR has enabled us to completely block the entry ofcoxsackievirus into cardiomyocytes and prevent allsigns of inflammatory cardiomyopathy.Selected PublicationsShi, Y., Chen, C., Lisewski, U., Wrackmeyer, U., Radke, M., Westermann, D.,Sauter, M., Tschöpe, C., Poller, W., Klingel, K., Gotthardt, M. (2009) Cardiacdeletion of the Coxsackievirus-adenovirus-receptor abolishes CVB3infection and prevents myocarditis in vivo. JACC 7;53(14):1219-26Lisewski, U., Shi, Y., Wrackmeyer, U., Chen, C., Fischer, R., Schirdewan, A.,Juettner, R., Rathjen, F., Poller, W., Radke, M., Gotthardt, M. (2008) The tightjunction protein CAR regulates cardiac conduction and cell-cellcommunication. JExMed 205(10):2369-79Raddatz, K., Albrecht, D., Hochgraefe, F., Hecker, M., Gotthardt, M. (2008) Aproteome map of murine heart and skeletal muscle. Proteomics8(9):1885-97.Radke, M., Peng, J., Wu, Y., McNabb, M., Nelson, O.L., Granzier, H., Gotthardt,M. (2007) Targeted deletion of Titin’s N2B region leads to diastolicdysfunction and cardiac atrophy. Proc. Natl. Acad. Sci. USA. 104(9), 3444-3449Peng J., Raddatz, K., Molkentin, J.D., Wu, Y., Labeit, S., Granzier, H., Gotthardt,M. (2007) Cardiac hypertrophy and reduced contractility in titin kinasedeficient hearts. Circulation 13;115(6):743-5Cardiovascular and Metabolic Disease Research 17