Molecular pathology of aortic aneurysm, allele-specific gene expression

Molecular pathology of aortic aneurysm, allele-specific gene expression

Introduction

The long-term interest of the Eriksson team is to investigate the underlying molecular mechanism of aortic aneurysm development. Aortic aneurysms are characterized by a degradation of the extra cellular matrix leading to a dilatation and eventually rupture of the vessel wall. The disease involves loss of elastin and remodeling of collagen, which are load bearing components of the vessel wall.

Major research focus

One of our main goals is to understand the underlying mechanism of the common aortopathy associated with a bicuspid aortic valve (BAV).  BAV is the most common congenital disorder of the aortic valve and is present in 1-2 % of the population. The presence of a BAV predisposes for progressive dilatation of the ascending aorta and thereby constitutes an increased risk of aortic aneurysm that may eventually lead to fatal rupture or dissection of the aorta. The prevalence of aortic dilatation in patients with BAV has been estimated to be as high as 50-70%. As yet, the pathophysiologic basis for the increased risk of aortic complications associated with BAV is not known.

Currently, two major hypotheses have been proposed to explain the more fragile aorta in BAV patients. The first is that a developmental abnormality or a genetic predisposition in BAV results in structural weakness of the aorta, which renders it more susceptible to aortic complications. The second or ‘’hemodynamic’’ theory argues that the chronic exposure of ascending aortic wall to higher blood flow velocities and eccentric flow jets due to the geometry of a BAV lead to a higher propensity of the BAV aorta to aorthopathy . Recently, an increasing number of researchers agree that both factors may contribute to BAV related cardiac complications.

Our research team’s goal is to understand how different signaling pathways interact to bring about the similarities and differences in molecular events of aneurysm formation in patients with BAV and patients with a normal tricuspid aortic valve (TAV). Besides inherited properties, we also study the possible dysregulation of biological pathways due to abnormal hemodynamic stress, which may contribute and/or lay the foundation for more fragility in BAV aorta. In order to do so, we integrate the core molecular biology with genomic, genetic and bioinformatics analysis. Importantly, we have collected large and well characterized unique biobank, including tissue biopsies from dilated and non-dilated aorta in addition to DNA, plasma and serum samples. Candidate genes and pathways are initially identified by transcriptomics, proteomics, epigenomics and genetic analyses. Functional evaluations are performed using cell culture and in vitro analyses. RNA sequencing is used to study allele-specific gene expression.

Collaborations

Affiliated to the team is Lasse Folkersen, PhD, Technical University of Denmark.

 

The study on BAV associated aortopathy is a close collaboration with the group of Professor Anders Franco-Cereceda at the Cardiothoracic Surgery Unit at the Karolinska University Hospital Solna. Studies on abdominal aortic aneurysm are in collaborations with Docent Joy Roy and Docent Rebecka Hultgren at the Vascular Surgery group, Karolinska University Hospital Solna (http://ki.se/en/mmk/star-stockholm-aneurysm-research-group).  

We are member of Leducq transatlantic network on BAV disease MIBAVA. The studies are supported by the Swedish Research Council and the Swedish Heart-Lung Foundation.

GruppChefPortlet

Team leader

Per Eriksson

E-mail

per.eriksson@ki.se

Job title

Professor

House

BioClinicum J8:20