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Regulation and function of the E3 ubiquitin ligases Muscle RING finger 1 and 3 in cardiac hypertrophy

Objective

Heart failure caused by cardiac hypertrophy is a growing epidemic and remains the most frequent cause of hospitalization in elderly patients in the European Union. However, molecular mechanisms leading to cardiac hypertrophy and its transition into heart failure are poorly understood. Maintenance of cardiac structure and function requires a precise control of protein synthesis and degradation; abnormalities in these processes can give rise to myopathies. The protein degrading ubiquitin proteasome system (UPS) and its muscle specific key enzymes Muscle RING finger (MuRF) 1 and 3 are activated during cardiac hypertrophy and heart failure. MuRF1 and 3 are essential for the degradation of structural proteins, such as myosin heavy chain (MHC), leading to a decrease in cardiac function and heart failure. MuRF inhibitors are therefore expected to prevent transition of cardiac hypertrophy into failure. This proposal aims to investigate the function and regulation of MuRF1 and 3 during cardiac hypertrophy. More specifically, the major hypothesis that the function of MuRF1 is mainly mediated through its E3 ubiquitin ligase activity will be investigated. First, the specific cysteine residue within the RING-finger of MuRF1 responsible for its E3 ubiquitin ligase activity will be identified. This residue will than be germ-line mutated and the hypertrophic response of mice lacking MuRF1s E3 ligase activity will be analyzed following aortic banding. Secondly, the domains within MuRF proteins mediating MuRF binding to their MHC target proteins will be investigated. Additionally, we aim to analyze if hypertrophic stimuli can regulate binding between MuRF1 and 3 and their target proteins. Finally, a cDNA expression screen will be employed to discover novel transcription factors and signal transduction pathways regulating MuRF1 expression during hypertrophy. Furthermore, our preliminary data showed that the MuRF1 promoter can be activated through the muscle-specific transcription fac

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

FP7-PEOPLE-IRG-2008
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Funding Scheme

MC-IRG - International Re-integration Grants (IRG)

Coordinator

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Address
Robert Rossle Strasse 10
13125 Berlin
Germany
Activity type
Research Organisations
EU contribution
€ 100 000
Administrative Contact
Andrea Winnefeld (Mr.)