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Young Talent

Saskia C.A. de Jager, Suzanne J.A. Korporaal, Antoinette Ouwerkerk

 

 

Autoimmunity at the crossroad of coagulation and inflammation in Atrial Fibrillation 

Saskia C.A. de Jager & Suzanne J.A. Korporaal

 

There is mounting evidence that, in addition to hypercoagulability, inflammation is an important contributor to atrial remodeling and AF development. Apart from that AF includes endothelial damage, which is reflected by the presence of autoantibodies directed against endothelial cells. Anti-endothelial cell autoantibodies can form immune-complexes, bind to damaged endothelium and induce platelet aggregation and subsequent thrombus formation.

Beyond their prominent role in hemostasis and thrombosis, platelets are increasingly recognized as being key players in several other biological disease processes, like fibrosis and immune regulation. Platelets interplay with damaged endothelium, interact with immune cells, provide the surface for activation of the coagulation system, and are the storage site of bioactive molecules involved in tissue injury and remodeling. Thus, plateletsmay be the key connecting inflammation with the progression of AF.

We hypothesize that the presence of chronic inflammation triggers auto-immune responses targeting the dysfunctional endothelium, thereby providing a substrate for platelet activation, culminating in an active contribution to the onset and progression of AF.

With this research grant, we will be able to create the fundament of our collaborative research line on the crossroad of autoimmunity and platelet-dependent responses in cardiovascular disease, which hopefully will create opportunities to generate additional funding.  

Researchers Profiles

Saskia C.A. de Jager: Assistant Professor and staff member in the Laboratory of Experimental Cardiology which is part of the Circulatory Health Program at the University Medical Center Utrecht and University of Utrecht. Specialized in cardiovascular immunology and experimental disease models. Over the last years I have focused on inflammatory mediators and circulating cells as biomarkers and causal players in cardiovascular disease, including atherosclerosis, myocardial ischemia/reperfusion injury and heart failure. The ultimate aim of my research is to identify novel immunomodulatory therapeutic targets for the treatment of CAD and Heart failure. 

 

Suzanne J.A. Korporaal: Assistant Professor and staff member in the Laboratory of Experimental Cardiology at the University Medical Center Utrecht and University of Utrecht. My research is part of the Circulatory Health Program. I am specialized in platelet biology in relation to cardiovascular disease, and platelet function diagnostics. Over the last years, my research focused on developing and standardizing a diagnostic platelet function test to determine platelet reactivity in relation to bleeding. At present, my research focuses on the development of atherosclerotic plaque erosion in women, with emphasis on the interaction of circulating cells with cells within the vasculature of the heart. Additionally, I aim to look for women-specific substances or abnormalities in the vessel wall and blood that are specific to the disease process. The ultimate aim of my research is to reveal the role of platelets in cardiac disease development and to develop tools for early identification of patients at risk of CAD, taking gender differences into account.

 

My name is Antoinette van Ouwerkerk and I did my masters in Biomedical Sciences at Leiden University, and currently I am a PhD at Amsterdam UMC. I am looking into the epigenetics of atrial fibrillation (AF), linking GWAS-identified variants and regulatory DNA to pinpoint causal variants.

The project that has been funded by the RACE V YTP grant is an in-depth study into the effect of a coding mutation in the cardiac transcription factor TBX5 found in a family with AF. Using a mouse model we will determine the effect of this point-mutation on expression in different cell populations of the heart with single cell RNA-seq. With this experiment we expect to find (altered) expression of direct and indirect target genes of TBX5 in cardiomyocyte sub-populations, fibroblasts and endothelial cells. Moreover, we will map the binding sites of the mutated transcription factor on the DNA, giving valuable insight into the potential mechanisms through which this mutation can add to AF development. I am very happy to get this wonderful opportunity to work with the RACE V consortium and contribute to the study of AF!