For a project that aims to study the impact of ADAMTS13 conformation on development of immune-mediated TTP, we are looking for an ambitious and pro-active PhD student.
Background and project
Sanquin is a knowledge-driven not-for-profit organisation that supplies life-saving products, focusing on the needs of the care sector. Through scientific research, Sanquin looks for and finds new solutions for medical problems in the field of transfusion medicine, hematology and immunology.
Within the Laboratory of Cellular Hemostasis cell biological, immunological and biochemical approaches are integrated to advance our understanding of the interplay between vascular, blood derived and immune cells with the hemostatic system. The current lines of research focus on the dissection the underlying mechanism of the auto-immune disorder thrombotic thrombocytopenic purpura (TTP) which targets the von Willebrand factor cleaving protease ADAMTS13 and the development of novel gene therapy and gene correction approaches for bleeding disorders. The different lines of research are strategically aligned with Sanquin’s mission to provide mechanistic insight into and develop novel therapeutic approaches for blood-related disorders.
In the context of the current PhD project will study the impact of ADAMTS13 conformation on development of immune-mediated TTP. It has previously been shown that ADAMTS13 circulates in an “open, active” conformation during the acute phase of immune TTP. Using molecular modelling technologies we have recently identified residues in the CUB1 domain that are crucial for maintaining ADAMTS13 in a closed conformation. We will use high resolution hydrogen-deuterium exchange in combination to further study the three-dimensional architecture of ADAMTS13 in its “open” and “closed” conformation. It was shown that patient-derived antibodies can induce changes in the conformation of ADAMTS13. To explore this interesting hypothesis we will generate a large panel of patient-derived monoclonal antibodies employing a novel mass spectrometry based “de novo sequencing”. The resulting panel will be interrogated for its ability to induce conformational changes within ADAMTS13. Apart from antibody-induced changes in protein conformation also post-translational modifications such as O-linked glycosylation and citrullination may contribute to conformational changes in ADAMTS13 that precede the onset and/or recurrence of thrombotic micro-angiopathies in patients with immune TTP. Overall our findings are expected to provide insight into the role conformational regulation of ADAMTS13 in the onset and recurrence of potentially life-threatening thrombotic events in patients with iTTP.
The PhD student will work within the Cellular Hemostasis group at Sanquin. The project is financially supported by the Landsteiner Foundation for Blood Transfusion Research. Our group is composed of several postdocs, 4-6 PhD students and technicians providing a highly dynamic research-environment which is embedded in the Department of Molecular Hemostasis. The current project is a collaboration between Sanquin, University of Utrecht, University Medical Center Amsterdam and the University of Maastricht. Prof. dr. A.B. Meijer will act as a co-PI on the project and will contribute expertise on hydrogen-deuterium exchange as well as “de novo sequencing” of human antibodies. The impact of O-glycans on ADAMTS13 conformation will be studied in collaboration with Dr. R. de Groot and Prof. M. Scully (University College London).
For further information, please contact Prof. dr. Jan Voorberg (firstname.lastname@example.org ). When interested send us your curriculum vitae and motivation letter (both in English) via e-mail: email@example.com explaining why this position interests you and how your skills match the profile. Applications can be done before February 22nd 2021.
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