Towards a better understanding of the molecular mechanisms underlying thoracic aortic aneurysms and dissections.

Expansion of a weakened region of the thoracic aorta (aneurysm; TAA) entails a high risk for aortic dissection/rupture. The latter events associate with severe internal bleedings, often resulting in sudden death. Over time, defects in more than 20 genes have been found to influence TAA predisposition. Yet, the disease's genetic and mechanistic picture is still far from complete, hampering development of amended diagnostic tools and therapies. We will further resolve the TAA puzzle by identifying novel protective and risk-inferring variants/genes and by examining their mode of action. Multiple lines of evidence suggest that some to be identified TAA genes locate to the X-chromosome. Recently, we indeed discovered TAA-causing defects in an X-linked gene, biglycan (BGN). Interestingly, in certain mouse strains protection from BGN-related TAA has been documented. We aim at mapping the protective factor and at translating its protective effect to men. A second genetic approach builds on the observation that in Turner syndrome (TS) girls lacking either the short X-arm (Xp) or the entire X-chromosome, TAA is strikingly frequent. The known X-linked TAA genes, however, locate to the long X-arm. Hence, we also aim at identifying novel Xp-located TAA genes in TS girls. Finally, to further delineate existing disease pathways or to discover novel ones, we will functionally characterize the identified protective and risk-inferring defects in patient samples and transgenic model systems.

Keywords:AORTIC ANEURYSM

Disciplines:Systems biology, Cardiac and vascular medicine