The Early Stage Researcher (ESR) will be trained within the prestigious Marie Skłodowska-Curie Innovative Training Network MINDSHIFT (Mechanistic Integration of vascular aND endocrine pathways for Subtyping Hypertension: an Innovative network approach for Future generation research Training) and will perform the research project entitled "Methylglyoxal: a reactive dicarbonyl sparking development of systolic hypertension" primarily at Maastricht University (UM) under the supervision of Prof. Casper Schalkwijk and Dr. Koen D. Reesink in close collaboration with partner institute Universidad de Computense, Prof. Marisol Fernandez-Alfonso, and with our private partner Quipu Srl, Dr. Elisabetta Bianchini.

Background & Objective

Large artery stiffening leads to systolic hypertension and is accelerated in diabetes. Advanced glycation endproducts (AGEs) are implicated in normative ageing, diabetes, and hypertension. Methylglyoxal (MGO) is a major precursor of AGE formation and MGO can be detoxified by glyoxalase-1 (Glo1). At the population level, plasma MGO is associated with increased systolic hypertension. The various pathways through which MGO could exert its effect on (accelerated) arterial stiffening have yet to be established. Possible routes include extracellular matrix cross-linking, vascular cell phenotypic changes, and perivascular tissue modulation of smooth muscle tone. This project is aimed at establishing how MGO modulates the cellular ageing process and, thereby, the arterial stiffening process.

Methodology

- Experimental models of Glo-1 overexpression and of ageing (smooth muscle and endothelial cell specific Ercc1∆/- mice) will be used.

- Biological and physiological effects of MGO across molecular-cell-tissue-vessel scales will be studied. Vascular reactivity will be determined by advanced pressure myography. Specific markers of cellular senescence will be included.   

- We have developed in-house a dedicated setup to quantify arterial biaxial mechanical properties as well as microscopic ultrastructure. In the project, a new approach needs to be developed to quantify smooth muscle tone ex vivo in intact vessel segments. In addition, smooth muscle cells will be characterised in vitro, enabling detailed phenotyping, including myogenic response and contractile markers like SM-MHC and smoothelin.

- We will include methods to capture and identify the paracrine role of perivascular fat tissue. MGO has been shown to impact perivascular fat metabolism and, in turn, perivascular fat has been shown to modulate smooth muscle cell function and phenotype.

- In addition to mechanistic studies, a pyridoxamine (vitamin B6)-based therapeutic approach to quench MGO will be developed and tested.

Collaborative secondments

For the project, three supporting secondments are planned to develop skills and widen the scientific scope. These include 2 months at the Fernandez-Alfonso lab at UCM on perivascular adipose tissue assays, 1 month at the Shiels lab at UGLA on cellular senescence assays, and 1 month at Quipu Srl on vascular ultrasound image quantification, in collaboration with MINDSHIFT projects 11 and 7.

Requirements

Please note there are strict *eligibility requirements* which apply to all Marie Skłodowska-Curie Early Stage Researchers. At the time of the appointment: Applicants must not have resided or carried out his/her main activity (work, studies, etc.) in the Netherlands for more than 12 months in the 3 years immediately before appointment under the project; Applicants shall also be in the first four years of their research careers at the time of appointment by the host organisation and have not been awarded a doctoral degree. For more information on Marie Skłodowska-Curie Innovative Training Networks (ITNs), please see: https://ec.europa.eu/research/mariecurieactions/node_en.

Qualifications: Master in biochemistry, experimental biology, or equivalent

Experience: Preferably combinations of: biological experimentation - tissue preparation - pharmacological studies - operating complex analytical equipment

Knowledge & skills: Cell culture, physiological measurements; in combination with animal research certification would be helpful

Abilities: Good communication skills, project planning and time management, integration of multi-disciplinary information and context

Attitude and disposition: Highly enthusiastic about research and willing to learn; creative and independent attitude; team worker

Fixed-term contract: 3 years.

You will be offered a salary plus mobility allowance and family allowance (if applicable) in line with the Marie Sklodowska-Curie Horizon 2020 requirements for Early Stage Researchers. Go to https://ec.europa.eu/research/mariecurieactions/sites/mariecurie2/files/msca-itn-fellows-note_en_v2.pdf  and http://www.maastrichtuniversity.nl > Support > UM employees for more information.

Please submit your application by filling in the vacancy form on the MINDSHIFT website.

Maastricht University

Maastricht University is renowned for its unique, innovative, problem-based learning system, which is characterized by a small-scale and student-oriented approach. Research at UM is characterized by a multidisciplinary and thematic approach, and is concentrated in research institutes and schools. Maastricht University has around 20,000 students and 4,700 employees. Reflecting the university's strong international profile, a fair amount of both students and staff are from abroad. The university hosts 6 faculties: Faculty of Health, Medicine and Life Sciences, Faculty of Law, School of Business and Economics, Faculty of Science and Engineering, Faculty of Arts and Social Sciences, Faculty of Psychology and Neuroscience.

Mindshift

MINDSHIFT is an EU funded PhD network coordinated by CARIM, School for Cardiovascular Diseases of Maastricht University, The Netherlands. MINDSHIFT brings together six university partners from across Europe to recruit a group of 15 of the best early stage researchers. The doctoral researchers will work together with senior researchers from across the network. Each candidate will be employed at one of the six universities and enrolled in a local PhD programme, while at the same time being part of an integrated research team and research project at network level.

MINDSHIFT offers a top-level interdisciplinary research programme to bridge the gap in understanding the dynamic interactions between vascular and endocrine pathways in hypertension, using an integrative framework approach fed by new data and insights from cutting-edge experimental and clinical studies.