Atherosclerosis, the primary cause of heart disease and stroke is a complex progressive disease with multiple genetic and environmental contributions. To date there have been no defined pathways which would explain how atherosclerosis could be reversed or indeed if such a pathway exists. The implications of this are important since most patients present with pre-established lesions and the therapeutic goal would be to reverse the lesion by discriminating the pathways for regression.

Our current programme of research investigates the fundamental mechanisms governing atherosclerosis regression. Our laboratory has established a novel model of atherosclerosis regression in vivo, achieved by administration of conjugated linoleic acid (CLA) apoE knockout mouse model of atherosclerosis. In addition, we have established Intravital Microscopy (IVM) as core facility in UCD. This system is employed to collect functional information about dynamic processes occurring in tissues and organ systems that are maintained in their natural state. For example, we have shown using this technology that CLA inhibits monocyte recruitment, monocyte-endothelial cell adhesion and trans-endothelial migration in the carotid and femoral arteries; providing novel in vivo insights into the molecular mechanisms mediated by CLA.

Our recent research has focused on the identification of distinct genes/pathways regulated by CLA that may yield further information as to how atherosclerosis can be reversed. To do this we employ an approach that involves confirmation of a phenotypic change in vivo by en face analysis and intravital microscopy. Using a transcriptomic and proteomic approach we then construct networks associated with the altered phenotype, followed by identification of central or ¿hub¿ genes which regulate the network. Using cellular models and functional assays we validate a functional role for these hub genes in vitro examining the effect of gene deletion or over expression on, monocyte-endothelial interactions, integrin regulation, adhesion, migration and foam cell formation. We then extend this study into human patients to seek evidence for regulation of the target/ ¿hub¿ genes in atherosclerotic disease progression.

Through this approach we have identified novel pathways. Some have complimentarity with pathways associated with atherosclerosis susceptibility for example we have recently characterized and ascribed a functional role for one target gene, SorLA in monocyte migration and have confirmed its regulation in human disease. In addition we have identified a PGC-1α regulated pathway associated with inhibition of monocyte migration and foam cell formation..  Our hypothesis is that this pathway can be further exploited to identify the key components involved in regression of atherosclerosis. Importantly, our data shows that the monocyte/macrophage cell is the cellular target through which CLA mediates its atheroprotective effect and suggests that alteration of monocyte/macrophage function is an important strategy in novel treatments for atherosclerosis.

Our work has a strong translational component and our current research is to determine if the novel targets, identified by us, they are modifiable in human disease. To this end, we have shown that macrophage specific deletion of PGC-1alpha promoted foam cell formation and accelerated atherosclerosis in vivo, suggesting that targeted manipulation of this network may retard the development of human disease. Importantly, our data indicates that PGC-1α is expressed in the macrophage/foam cells of atherosclerotic plaques from both symptomatic and asymptomatic patients where its expression is inversely associated with disease progression. The importance of this is that it has facilitated the identification of novel ¿druggable¿ targets for more effective therapies, which can now be achieved through our collaboration with Industry.

Research Team

Dr. Denis Barry, Post Doctoral Research Fellow

Dr. Cathal McCarthy, Post Doctoral Research Fellow
 
Dr. Eugene Demosey, Post Doctoral Research Fellow 

Ms. Monica de Gaetano, PhD Student

Mr. Declan Mooney, PhD Student

Ms. Karen Haughton, PhD Student

Mr. Will James, Research Scientist

Prof Aldons Jake Lusis,
Dept. Human Genetics, UCLA, CA, USA

Prof. Chrostopher Glass,
UCSD, USA 

Ms. Mary Barry,
Consultant Vascular Surgeon, SVUH, Diblin

Prof. Matthew Griffin,
Professor of Transplant Medicine, NUIG, Galway 
 
Prof. Paola Patrignani,
University of Chietit, italy