Advanced Medical Scientist-Programm 2021

Thema: "The contribution of ceramides to cardiac injury"

Zusammenfassung:
Metabolic perturbations are the hallmarks of the failing heart. In the injured myocardium, accumulation of ceramides is observed. It is well-documented that inhibition of ceramide synthesis effectively lowers ceramide levels and rescues cardiac function. However, it remains inconclusive if accumulation of ceramides is sufficient to cause cardiac dysfunction in the absence of injury. In addition to metabolic disorder, disrupted protein homeostasis has also been reported in the injured myocardium. A recent study suggests that lipid metabolism coordinates protein homeostasis and that ceramides play critical role in regulating unfolded protein response. Nevertheless, their specific role in protein homeostasis in heart is not yet clear. Specific ceramide species that accumulate in the failing heart and coordinate the protein homeostasis response are the very-long-chain ceramides whose production is dependent on the ceramide synthase isoform 2 (cers2). Therefore, the goal of the project is to use a tetracycline-inducible Tet-on, cardiac-specific cers2 overexpression transgenic mouse model in combination with in vitro culture system to examine contribution of ceramide accumulation to cardiac damage and to delineate the link between ceramides and protein homeostasis.