ORGANISATION/COMPANYStichting VUmc (AmsterdamUMC-location VUmc ) (The Netherlands)
RESEARCH FIELDBiological sciences › OtherMedical sciences › Medicine
RESEARCHER PROFILEFirst Stage Researcher (R1)
APPLICATION DEADLINE31/12/2020 23:00 - Europe/Brussels
LOCATIONNetherlands › Amsterdam
TYPE OF CONTRACTTemporary
HOURS PER WEEK40
OFFER STARTING DATE01/02/2021
EU RESEARCH FRAMEWORK PROGRAMMEH2020 / Marie Skłodowska-Curie Actions
MARIE CURIE GRANT AGREEMENT NUMBER859974
EDUC8 is an Innovative Training Network (ITN) funded by the European Union Horizon 2020 Programme. The EDUC8 training network represents a novel, pioneering platform for studying the immunogenicity of therapeutic pro-coagulant factor VIII (FVIII) in patients with haemophilia A (HA). It includes leading scientists from academia and industry. The EDUC8 training network offers doctoral research projects (PhD projects) for eight early stage researchers (ESRs). The research topics range from fundamental to translational science, and aim at identifying drug- and patient-related risk factors for the development of neutralizing anti-FVIII antibodies, and at developing innovative protocols for inducing tolerance to FVIII. The successful applicants will receive training in basic immunology, haemostasis research and bioinformatic approaches, clinical haemostasis, project management, entrepreneurship, healthcare economics, ethics and marketing. The interaction between biologists, clinical experts, healthcare professionals, industry and patients’ organizations is central to EDUC8. It will expose ESR to complex issues in bench-to-bedside research from different perspectives. Graduates from EDUC8 will be highly skilled, entrepreneurial and broadly-trained experts, equipped with innovative and beyond state-of-the-art proficiency on the exponentially expanding area of “immunogenicity of biotherapeutics”.
Participating in EDUC8 offers early stage researchers many unique opportunities, including:
- A project as Marie Skłodowska Curie trainee in one of the participating institutions with the intention of receiving a doctoral degree (PhD).
- State-of-the art, exciting research in an international consortium with highly integrated research projects.
- Expert training in basic and translational immunology.
- At least three months of research training in the lab of another consortium member, mostly in a different EU country than the country where most of the project will take place.
- Training in both academic and commercial research environments.
- Salary according to EU guidelines for Marie Skłodowska Curie trainees, including mobility payments and family allowances where applicable.
Eligible candidates must:
- hold a Master’s degree or equivalent in a field of science relevant to their chosen project (see below)
- demonstrate a history of academic excellence
- demonstrate an affinity for Basic Immunology and Translational Immunology, Haemostasis or Translational Research
- speak and write fluently in English
- have less than 4-years previous research experience and not hold a doctoral (PhD) title
- have not been resident in the Netherlands where the host institution is located for more than 12 months in the 3 years before recruitment
- be available to start their project no later than 1st February 2021
Individual Project details
ESR6: Induction of tolerance to therapeutic factor VIII in HA by modification with a 2,3 sialic acid
Hosting Institution: Stichting VUmc (AmsterdamUMC-location VUmc ) (The Netherlands)
Supervisor Prof Yvette van Kooyk
Subject area: Molecular cell biology and Immunology, Glycobiology
Project-specific selection criteria A master degree Biomedical Sciences or related, knowledge of immunology, experience with (primary) cellular responses and molecular biology, interest in chemical immunology is a plus, flexible, team player, able to interact with scientists from different backgrounds, departments, and institutions, excellent communication skills in English (both written and verbal)
Introduction: The GlycoDCTM technology is developed by Amsterdam UMC/Stichting VUmc, which allows modification of antigens with an α2-3-sialic acid. α2-3-sialic acid-conjugated antigens (Sia-Ag) target dendritic cells by specific binding to inhibitory sialic acid-binding Ig-type lectin (Siglecs) receptors. Application of this technology to models antigens, such as ovalbumin or the myelin oligodendrocyte glycoprotein-derived peptide (MOG35-55), facilitated uptake by dendritic cells of the Sia-Ags, and promoted naïve CD4+ T cell differentiation to regulatory T cells in vitro and in vivo. Importantly, Sia-Ag stimulated DCs were able to dampen the functioning of established effector T cells, implying that antigen sialylation is a highly attractive strategy to inhibit ongoing inflammatory immune responses.
Aims: The goal is to exploit the GlycoDCTM technology to induce preventive or therapeutic antigen-specific tolerance to therapeutic FVIII. ESR6 will couple recombinant human B domain-deleted FVIII as well as immuno-dominant FVIII peptides to 2,3-sialic acid (Sia-FVIII/peptides) and will generate several Sia-FVIII/peptides candidates. ESR6 will confirm the binding of Sia-FVIII/peptides candidates to siglec-E on mouse splenic DCs and to siglec-9 on immature human MODCs, determine the efficiency of Sia-FVIII/peptides uptake and analyze the maturation profile of DCs by measuring cytokine release and phenotypic analysis by flow cytometry. ESR6 will determine the capacity of Sia-FVIII/peptides-loaded DCs to generate de novo functionally proficient CD4+Foxp3+ Tregs both using mouse and human cells. Using the most promising Sia-FVIII/peptides candidates and in secondments with partner B1 and Partner B4, ESR6 will then investigate the in vivo tolerogenic effect of Sia-FVIII/peptides both in preventive and therapeutic experimental protocols.
Expected Results: The results will confirm the capacity of glycosylated immunodominant FVIII-derived peptides and/or glycosylated recombinant FVIII to induce tolerance to therapeutic FVIII. The results will confirm the efficiency of binding of Sia-FVIII to the targeted siglecs, internalization efficiency, tolerogenic cytokine profile and induction of FVIII-specific Tregs.
Planned secondment: ESR6 will be seconded at B1 for 3 months from M29 (INSERM, HLA-DR Tg FVIII-KO mice), B4 for 3 months from M34 (GUF, FVIII-KO mice) and 4 months at DC4U under the supervisions of Dr. Sébastien Lacroix-Desmazes, Dr. Christoph Königs and Ineke Rijnhout respectively.. The secondments will have the following objective: i) injection of Sia-FVIII/peptides to relevant animal models and validation of tolerance induction to therapeutic FVIII by ii) analysis of the antidrug antibody levels in plasma iii) functional coagulation assays iv) immunological studies including T and B cell phenotyping and functional assays.
Enrolment in Doctoral degree(s): ESR6 will be enrolled in the VU University, Amsterdam (PX), The Netherlands
Project-specific selection criteria: A master degree Biomedical Sciences or related, knowledge of immunology, experience with (primary) cellular responses and molecular biology, interest in chemical immunology is a plus, flexible, team player, able to interact with scientists from different backgrounds, departments, and institutions, excellent communication skills in English (both written and verbal)
Recommended reading:  Lübbers J et al. (2018) Modulation of Immune Tolerance via Siglec-Sialic Acid Interactions. Front Immunol.  Perdicchio M, et al. (2016) Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells. Proc Natl Acad Sci U S A.  Perdicchio M et al. (2016) Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells. Oncotarget.  Scott DW et al. (2019) Factor VIII: Perspectives on Immunogenicity and Tolerogenic Strategies. Front Immunol.  Läubli H et al. (2019) Sialic acid-binding immunoglobulin-like lectins (Siglecs) detect self-associated molecular patterns to regulate immune responses. Cell Mol Life Sci.
ESR will be given an employment contract for 36 months by their host institution. ESR will be entitled to full employee benefits and inclusion in social security schemes of the host nation. ESR will be compensated according to the general conditions of the EC MSCA and specifically those conditions relating to ESR participating in ITN.
Experience eligibility requirement:
Eligible applicants must:
- hold a Master’s degree or equivalent in a field of science relevant to their chosen project
- demonstrate a history of academic excellence
- demonstrate an affinity for Immunology and Molecular Biology
- speak and write fluently in English
- have less than 4 years’ previous research experience and not hold a doctoral (PhD) title
Mobility eligibility requirement: The fellow must not have resided in the country where the research training activities will take place for more than 12 months in the 3 years immediately prior to the recruitment date (and not have carried out their main activity (work, studies, etc.) in that country).
- In addition to basic and practical knowledge in immunology, the fellows must demonstrate team spirit, sense of commitment, creativity and passion, and excellent communication skills in English (both written and verbal)
EDUC8 will select ESR through a 2-step recruitment process.
Candidates should submit their application for their top two preferred research projects. Applications (in English) should include:
1) an updated CV
2) a letter of motivation for the position;
3) at least 1 reference letter (in English) from one former supervisor
4) the scan of the degree (usually the Master Degree) which would formally entitle him/her to embark on a doctorate
5) transcripts of records
The candidates will be evaluated on the basis of the received documents and the best 8 candidates will be invited for a Skype interview and ranked The top 2 candidates will be invited for a second interview and the final decision will be communicated shorthly
A master degree Biomedical Sciences or related, knowledge of immunology, experience with (primary) cellular responses and molecular biology, interest in chemical immunology is a plus, flexible, team player, able to interact with scientists from different backgrounds, departments, and institutions, excellent communication skills in English (both written and verbal)
Project-specific requirements are detailed for each individual project
EURAXESS offer ID: 582984
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