Fingerprinting proteoglycan turnover by ADAMTS proteases in the cardiovasculature

Thoracic aortic aneurysms and dissections (TAAD) is a lethal, silent disease, characterised by the accumulation of proteoglycans (PGs), structural macromolecules playing a major role in the integrity and function of cardiovascular tissues. ADAMTS proteases are responsible for the turnover of aortic PGs.

However, surprisingly little is known about the mechanisms behind their proteoglycanase activities, both clinically and biochemically.

In this fellowship, I will apply proteomics to investigate how specific ADAMTSs proteases regulate PG levels in human aorta. I will generate complete proteolysis maps of versican, aggrecan and biglycan for ADAMTS-1, -4, -and -5.

ADAMTS-specific cleavage fragments will be confirmed in murine models where each ADAMTS has been knocked out individually.

I will then perform proteomic analysis of aortic PG extracts from patients with TAAD to identify the presence of these fragments.

Combined, the multiple proteomic approaches will allow me to determine the relative importance of each ADAMTS family member for proteolysis of vessel wall PGs, and most importantly, build a prospective link to TAAD.