Our Research
Atherosclerotic plaque in reality
Atherosclerosis is the major aetiology behind complex CVD, leading to high morbidity and mortality due to plaque rupture, myocardial infarction and stroke. Despite decades of research into the mechanisms of atherosclerotic plaque instability, there are still no available biomarkers specific for prediction of plaque rupture events, nor targeted therapies to alleviate plaque burden in patients. An urgent clinical need exists to provide novel diagnostic and therapeutic targets for improved, personalised management of atherosclerosis.
The research in this field has greatly expanded in recent years, mainly due to the rapid development of novel methods for longitudinal cellular lineage tracing in mice models of vascular disease in vivo and large-scale single-cell technologies. The research encompassed by our Group is primarily experimental and includes all these components, combined with clinical aspects and integrative systems biology analyses, as well as proof-of-concept interventional animal studies to test the druggability of potential therapeutic targets.
We strive to:
Identify and investigate previously unknown key molecular and cellular mechanisms of vascular injury and disease related to smooth muscle cell trans-differentiations
Harness those mechanisms for translation into novel biomarker and drug pipelines, with particular focus on ameliorating atherosclerosis and adjoined vascular pathologies
Atherosclerotic plaque seen by AI
Research Projects
Harnessing the potential of smooth muscle cells for treatment of vascular diseases
Smooth muscle cells build the vessel wall and are normally programmed to contract and regulate blood pressure. But they also play an important role in vascular diseases, such as atherosclerotic plaque rupture that can lead to heart attacks and strokes, or in stent implantation and other surgical interventions that can cause vascular damage. We still don't know enough about what drives these processes and how smooth muscle cells can be used to heal vascular injuries.
Our project focuses on understanding different smooth muscle cell subtypes and developing tailored treatment options based on their mechanisms. We aim to investigate how smooth muscle cell function is regulated in diseases such as atherosclerosis. We are doing this by analyzing molecules in atherosclerosis plaques from biobanks of patients who underwent vascular surgery at Karolinska University Hospital since 2002. We use advanced molecular analyses, bioinformatics and biostatistics to examine candidate molecules from these samples. The identified molecular candidates are then studied in experimental models in the research lab. We also work to validate the candidates in other international biobanks through collaborations, to asure their value as therapeutic targets or biomarkers to predict risk and make diagnostic assessments.
By understanding the mechanisms that regulate the properties of smooth muscle cells, we will be able to develop new strategies to prevent complications that can occur during stent implantation and vascular diseases such as heart attacks and strokes.
2. The function and therapeutic targeting of proprotein convertases (PCSKs) in vascular disease
By molecular profiling of human atherosclerotic plaques, we discovered in 2013 that Proprotein Convertase Subtilisin Kexin 6 (PCSK6) is one of the most enriched molecules in lesions from patients with stroke symptoms, localized to plaque smooth muscle cells and induced by growth factors and inflammation. Further investigations in PCSK6 knock-out mice, murine vascular injury models, ex vivo and in vitro studies in primary vascular tissues and cells, identified the functional link among increased PCSK6 levels, vascular remodeling via MMP2/MMP14 and smooth muscle cell activation towards proliferation/migration in disease.
Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-6, FURIN, MBTPS1, and PCSK9. These proteases have been poorly studied in vascular disease, although their role in growth factor processing and cell activation is well established in cancer. Apart from PCSK9, which is a major target for lipid lowering in patients with high LDL cholesterol, little is known about the role of other PCSKs in vascular disease. We aim to investigate in detail the expression landscape and druggability potential of the entire PCSK family for CVD.
We are conducting the first comprehensive exploration of PCSK-dependent mechanisms in vascular disease, particularly focusing on their role in smooth muscle cells and utilizing an integrative systems approach with deep profiling from independent human cohorts, combining early and advanced atherosclerosis, coronary artery disease, aortic aneurysm and experimental in vivo and in vitro studies. In collaborations with pharmaceutical industry, candidates with translational potential are further evaluated as biomarkers or therapeutic targets, to improve care of vascular patients.
