Sex-specific functions of mTORC1 and mTORC2 in cardiac hypertrophy

• Antragstellerin: Professorin Dr. Duska Dragun (†)
• Fachliche Zuordnung: Nephrologie
• Förderung: Förderung von 2008 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 60843499

Mammalian target of rapamycin (mTOR) functions as a catalytic subunit of two multiprotein complexes - mTORC1 (mTOR in complex with raptor) and mTORC2 (mTOR in complex with rictor). mTOR is a nodal point of intracellular signaling in both adaptive and maladaptive cardiac hypertrophy responses. We aim to further understand how gonadal hormones contribute to regulation of fine balance between mTORC1 and mTORC2 signaling outputs. Our data from the first funding point towards crucial role of ERß in female sex restricted antihypertrophic mTORC2 effects. We now aim to extend our studies on androgen receptors in our maladaptive model. In order to address sex-specific utilization of mTORCs and their influence on cell size control in terms of cell growth, survival, autophagy, and senescence we will use cardiomyocyte restricted mice deficient for mTORC1 defining component raptor and for mTORC2 defining component rictor and challenge them with mineralocorticoid excess. Cell culture studies using combination of loss-of-function studies and phenotypic rescue with gain of function approach will complement in vivo studies in order to identify new signaling components up-stream and down-stream from mTORC1 and mTORC2 in the sex-specific and hormonally dependent or independent context.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 1054: Sex-specific mechanisms in myocardial hypertrophy