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Pathomechanistic study of biglycan mutations in aortopathy development.

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. Progressive dilatation of the aorta leads to the development of thoracic aortic aneurysms and dissections (TAADs), which are often asymptomatic but predispose to aortic dissection and rupture. The latter are associated with high mortality rates. In 2017, I identified mutations in BGN (Biglycan), an X-linked gene, as a novel cause of a severe syndromic form of TAAD, which shows clear clinical overlap with Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), and is now designated as Meester-Loeys syndrome (MRLS). Based on the current knowledge, it remains unknown which molecular mechanisms explains how loss-of-function mutations in BGN lead to syndromic TAAD (MRLS). Within this project, I aim to further unravel the pathomechanism underlying MRLS using (single cell) transcriptomic approaches in an in vivo BALB/cA Bgn KO mouse model and validate these findings in an in vitro human iPSC-VSMC model. The expected results will be beneficial for genetic counselling and clinical follow-up of the families. Furthermore, they can lead to the development of more personalized preventive therapeutic strategies. In the long run, I anticipate that our research group will also use these mouse and cell models for drug compound screenings for syndromic TAAD.
Date:1 Jul 2022 →  Today
Disciplines:Vascular diseases