We seek a PhD student to investigate the role of DAMPs in the pathogenesis of platelet refractoriness, The project forms part of a research program (3 PhD students) on the immunological aspects of platelet transfusion. The research will take place within the Department of Immunopathology at Sanquin as well as at the Academic Medical Center (AMC). For the purpose of the project we will closely collaborate with Dr. Pieter van der Meer from the Department of Clinical Transfusion Research. 

Platelet refractoriness is associated with morbidity and mortality in patients receiving myeloablative chemotherapy. Preformed, or newly formed anti-HLA or anti-human platelet antibodies that arise after repetitive transfusion of 5-donor-platelet concentrates, induce refractoriness in a significant percentage of these patients. However, only in part of these patients the transfusion of HLA- and/or HPA matched platelet concentrates results in satisfactory platelet recovery, indicating that other factors than anti-platelet antibodies must contribute to refractoriness. Systemic inflammation forms an inherent feature of myeloablative chemotherapy, since widespread cell damage induced by chemotherapy occurs. This is accompanied by the release of DAMPs, such as cell-free DNA, histones, and DNA-binding proteins. Neutropenic fever further complicates the pancytopenic period after myeloablative chemotherapy. In addition, DAMPs may potentially also arise in the platelet product during the manufacturing process or during storage, and contribute to systemic inflammation in the recipient of the platelet product, and hence refractoriness. We have recently described that Factor VII activating protease (FSAP) induces the release of nuclear DAMPs (e.g. nucleosomes) and subsequently neutralizes the cytotoxic effects of these DAMPs, i.e. histones through their degradation. The aim of the current project is to investigate the role of systemic inflammation and DAMPs release in the pathogenesis of platelet refractoriness, and to study the potential therapeutic effects of FSAP to neutralize these DAMPs. The present project will make use of a translational approach, combining in vivo studies in mice and functional studies with human platelet concentrates in vitro. 

Where you will work:

The research group of Prof. Sacha Zeerleder and Dr Brenda Luken, in the department of Immunopathology, studies the inflammation induced by damage-associated molecular pattern (DAMPs), e.g. cell-free DNA, histones, and heme. Our research focuses on the specific consequences of the various DAMPs in the pathogenesis of inflammation, the mechanisms of DAMPs release, and how circulating DAMPs may be neutralized to overcome their detrimental effects.

We are looking for highly motivated candidates with:

• An academic background with profound experience in cell biology, protein biochemistry and protein purification techniques and possess an “artikel 9” certificate;
• An independent candidate with a collaborative nature;
• A strong affinity for multidisciplinary research;
• English language skills, both written and oral, are required.

• pay and working conditions conform CAO Sanquin;
• working hours are fixed by mutual agreement;
• a temporary appointment for a period of 4 years;
• a 36-hour week;
• 8,33% end-of-year bonus;
• by full-time employment at least 201 vacation hours;
• reimbursement of travel expenses.