Role of Cand2 in cardiac pathophysiology

• Applicant: Professor Dr. Mirko Völkers
• Subject Area: Cardiology, Angiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455752792

Pathological cardiac hypertrophy predisposes to the development of heart failure (HF) and is frequently a consequence of ventricular pressure overload, myocardial infarction, or inherited cardiomyopathies. Pathological hypertrophy is associated with strong increases in protein synthesis that lead to enlargement of the heart within days after pressure overload.The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master regulator of protein synthesis. Importantly, previous studies have emphasized the central role of mTORC1 for translational regulation and for HF development and progression. mTORC1 activation enhances mRNA translation by induction of rRNA transcription, stimulation of ribosomal protein biosynthesis, by phosphorylation of translation initiation factors, but also controls translational of specific networks of mRNAs that are required to stress adaptation. The mTORC1-dependent induction of cellular remodeling underlines its significance in HF and importance as a therapeutic target. Since a pharmacological inhibitor of mTOR, rapamycin, improves cardiac function, but also causes side effects it is a great of importance to identify specific mTORC1 targets for innovative treatment options. A newly developed experimental procedure has been used to perform a cardiac myocyte genome-wide analysis of mTORC1-dependent post-transcriptional gene expression control at the level of mRNA translation. This approach identified Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene dependent on the activity of mTORC1 during pathological stress both in vitro and in vivo. Cand2 is a muscle specific protein, but its function in differentiated cardiac myocytes is still unknown. The overall goal of this proposal is to delineate the critical importance of the mTORC1-dependent translational control of Cand2 expression during pathological cell growth with significant impact on cardiac function. Specific aims are designed to comprehensively understand Cand2 expression regulation and its contribution to HF, both in vitro in cultured cardiac myocytes and in vivo in adult murine hearts. We aim to characterize the molecular mechanisms of mTORC1-dependent translational control of Cand2 expression during pathological cell growth. We propose that cellular remodeling and cardiac function is regulated by Cand2 expression and we will develop therapeutic strategies. In the last aim, we will define the molecular function of Cand2.

• DFG Programme: Research Grants