Aging with marfan syndrome - possible survival benefit of rapamycin in a murine model of marfan syndrome.

• Applicants: Professor Dr. Andreas H. Wagner; Dr. Marcin Zaradzki
• Subject Area: Cardiac and Vascular Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518471776

Marfan syndrome (MFS) is a rare disease of the connective tissue. Due to mutations in the fibrillin-1 gene, elastin-associated microfibrils are disturbed. This leads to structural instability of the connective tissue and an increase in the matrix metalloproteinase and TGF-ß abundance in the extracellular matrix (EZM). As a result of MFS, the most common cause of death is early aortic ectasia and aneurysm, which usually lead to aortic dissection. It can be assumed that mTOR (mechanistic target of rapamycin) has a decisive role in the formation of proteases and the restructuring of the ECM. The homozygous fibrillin-1 deficient mouse (mgR/mgR) is accepted as a small animal model for MFS. Preliminary studies on explanted aortic cells of mgR/mgR mice showed that mTOR activity is significantly increased and that there must be a permanent correlation between fibrillin-1 gene defect and mTOR. In addition, the median survival of treated older Marfan mice was shown to be significantly prolonged for the first time. With regard to our preliminary work, the main focus of this project is to clarify the suitability of rapamycin as a low-dose permanent medication in Marfan patients (“low-dose therapy”). Since there are only surgical treatment options for the symptomatic complications of Marfan syndrome, this would be an important causal treatment approach to prevent the onset/progression of aortic elastolysis. In addition, the following questions are to be experimentally clarified: · How does protein expression of inflammatory and structural proteins in Marfan mice change over time? · Can a rapamycin-mediated mTOR inhibition be used as rescue therapy for already pronounced aneurysms? · How does mTOR inhibition by rapamycin stabilize the aorta? There is evidence that the metabolism of vascular smooth muscle cells changes with age, which may affect the course of disease in older people. Therefore, an investigation of these aging processes is essential. The animal experiments aim to demonstrate the life-prolonging effect of rapamycin therapy in young female and male animals in survival groups. In addition, rapamycin will be administered to a group of animals as a low-dose continuous medication starting from the second week of life to reveal potential differences from short-term therapy. The other groups are used for structural and histological examination of the aorta. The final question, how rapamycin stabilizes the aortic wall, is to be answered with the help of the previously explanted aortic tissue. Priority will be given to investigating and verifying the target proteins identified during the preliminary work using a protein profiling approach. In summary, we want to investigate the role of aging in the MFS model of the mgR/mgR mouse, as well as the effect of rapamycin on the survival of the animals.

• DFG Programme: Research Grants