Rapamycin induced Inhibition of aortic elastolysis in a murine model of marfan syndrome

• Applicant: Dr. Marcin Zaradzki
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421971899

Marfan syndrome is a complex genetic disorder with a pleiotropy of symptoms caused by a mutation in the fibrillin-1 gene. The leading symptoms are vascular disorders, lens luxations and skeletal deformations. There is still no systemic therapy for the life threatening complications like aortic aneurysms and dissections. The pathophysiology of this disease’s vascular components can be explained by instability of the microfibrils in the aortic media. The instability is due to an abnormally high expression and activity of matrix metallo proteinases (MMP) from the aortic smooth muscle cells in the media. This group of enzymes degrades the elastin fibers and through a fragmentation of the microfibrils leads to a higher TGF-β bioavailability. All of these findings ultimately cause a destabilisation of the aortic wall. The reason for a higher MMP expression is rooted in a higher activity of TGF-β driven signalling pathways. One of the associated signalling cascades is the mTOR (mechanistic target of rapamycin) pathway. mTOR is a highly conserved protein which regulates central cell mechanisms as cell differentiation, cell proliferation and apoptosis. In addition, literature reviews suggest that there is a correlation between the expansion of inducible aortic aneurysms in animal models and the inhibition of mTOR via rapamycin.I was able to show in preliminary experiments that there is also a higher activity of mTOR in cryosections of the aortic wall of murine Marfan mice.Therefore, the working hypothesis of this project is that hereditary aortic diseases like Marfan syndrome are mTOR dependent. For a closer understanding of the underlying mechanisms several experiments are needed. First a rapamycin induced inhibition of mTOR in vitro in murine aortic smooth muscle cells (mAoSMC) from Marfan mice will be performed. This should provide the insight of whether the mTOR inhibition is capable of reducing the expression and activity of MMPs in the cell culture. After this proof of concept in vivo experiments will be carried out. The plan here is to inhibit elastolysis in the Marfan mouse and detect mechanistic changes in the aortic wall structure. In addition I aim to reduce or totally inhibit the expansion of aortic aneurysms for a survival benefit.Up till now the only therapy available for Marfan patients is the surgical correction of the expanding aortic aneurysms. No systemic therapy has so far lived up to its promises. In contrast rapamycin and other mTOR inhibitors have been already well established as imunmodulators in transplantation medicine. With a successful rapamycin-dependent inhibition of aortic aneurysm formation a systemic therapy could be optimized.

• DFG Programme: Research Grants