Dr. Raya Saif Al-Maskari (Lecturer of Pharmacology) had presented her PhD work entitled “Artery Stiffness: Genes & Pathways” as a knowledge sharing activity with the staff of Pharmacy Department.
Aortic stiffness has emerged over the last decade as an important predictor of cardiovascular end-points. As with most complex traits, aortic stiffness has a multifactorial aetiology and its genetic architecture is diverse, including many common variants with subtle effects. The aim of my PhD work was to expand on the existing knowledge of the genetic landscape that governs this trait, which may help uncover novel targets that may be amenable to pharmacological interventions. I employed multiple approaches to identify the genetic basis of the stiffening mechanism using a large repository of human donor aortas. In the first part of the study I examined the molecular basis of a pedigree with multiple cases of aortic aneurysms and identified a mutation resulting in an overshoot of TGF-β signaling in the aorta. In the second part, I sought to provide a biological basis for a genetic locus that had been identified in the largest-scale GWAS (genome-wide association study) meta-analysis of aortic stiffness. The locus lies in a gene desert that overlaps regulatory enhancers for B-cell CLL/lymphoma 11b (BCL11B). My work found that BCL11B transcript in the aorta strongly correlated with lymphocyte markers, suggesting an immune-mediated association of BCL11B with aortic stiffness. Finally, I explored the trait from a candidate-gene perspective and investigated the role of two extracellular matrix proteins, aggrecan and fibulin-1 in the stiffening mechanism. The most important finding was the discovery that aggrecan undergoes an age-dependent proteolytic degradation, which provide a compelling interpretation for many of the age-related changes observed in the arterial wall matrix. This finding may generate novel pharmacological therapies that halt or reverse the stiffening process by preventing loss of aggrecan from the arterial wall.
Head – Pharmacy Department