mTOR in metabolic cardiomyopathies

• Applicant: Dr. Christian Oeing
• Subject Area: Cardiology, Angiology ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 512512276

Heart Failure with preserved ejection fraction (HFpEF) and diabetic cardiomyopathy are marked by a substantial overlap regarding pathogenesis. HFpEF is one of the leading problems in cardiovascular medicine with minimal therapeutic options. It is the aim of this study to better understand the pathogenesis of this deadly disease, and to develop and test novel therapies. The protein complex mechanistic target of rapamycin (mTOR) is involved in the development of many different diseases. In the failing heart mTOR is known to be hyperactivated, but its role in the diabetic heart and HFpEF remains controversial mostly due to lack of adequate models. Complete knockout models or transgenic overexpression models remain rather artificial. In data generated in the U.S. and Berlin, we developed a novel genetic mouse model, in which a more physiological fine-tuning of the mTOR complex can be achieved to regulate mTOR in both directions – to inhibit or hyperactivate. But, this mechanism is only active when the cell is exposed to a pathological stimulus. The healthy heart remains intact. In this project we study the influence of mTOR signaling in the metabolically challanged heart. We already found exciting insights showing that mTOR (hyper-)activation contributes to a worsening of diabetic cardiomyopathy as well as HFpEF while mTOR suppression in these hearts minimized disease progression. Altered autophagy and a shift in cell metabolism might be responsible for this mechanism. Endothelial dysfunction supposedly plays an important role in the development of these diseases as well and will be examined via a unique knock-in model. This we would like to investigate further, test new drugs to exploit this cellular mechanism to ultimately contribute to find a novel therapy for all the patients suffering from these common conditions.

• DFG Programme: Independent Junior Research Groups
• International Connection: USA
• Cooperation Partner: Professor Dr. David A. Kass