Job - PhD student, FHML/School for Cardiovascular Diseases (CARIM)/Pharmacology

Heart failure is one of the leading causes of death in the Western world. Myocardial infarction (MI) frequently leads to excessive dilatation of the left ventricle, resulting in heart failure. Current pharmacotherapy can only slow down the progression of heart failure, making prevention of its development the best therapeutic option available. Recently, the myofibroblast has been identified as a potential therapeutic target to stop or even reverse left ventricular dilatation after MI: This cell type combines smooth muscle-like contraction with extracellular matrix synthesis. These features counteract dilatation of the scar tissue in the infarct area and repair the damage invoked to the extracellular matrix by repetitive cardiac contraction. There is still ample room for novel therapeutic interventions that are aimed specifically at the myofibroblast.

Infarct healing, myofibroblast biology and relevant signal transduction pathways have extensively been studied. We have identified the overexpression of frizzled-1 and -2 receptors, components of the Wnt/frizzled signaling pathway, in myofibroblasts. Genetic interventions inhibiting Wnt/frizzled signaling at different levels were shown to improve cardiac function after MI. However, the therapeutic relevance of these observations was limited, because at that time frizzled receptor antagonists were not available.

Recently, we have developed UM206, a high affinity antagonist for frizzled-1 and -2 receptors in mouse, rat and man. In mice, administration of UM206 for 5 weeks starting at the induction of MI resulted in a significant reduction in infarct dilatation,

a 4-fold increase in myofibroblast numbers in the infarct are and an increase in ejection fraction from 17±2 to 31±2%. Moreover, death due to heart failure was completely absent in the UM206-treated mice but occurred in 21% of the saline-treated mice. Based on this initial study, we formulated the hypothesis that frizzled-1 and -2 receptors are a powerful therapeutic target for treatment of MI and prevention of heart failure development.

The aim of this project is to further explore the therapeutic potential of the Wnt/frizzled pathway in preventing heart failure after MI. We will quantify the expression of Wnt/frizzled components in different animal models, to study a causal relationship with myofibroblast numbers and infarct dilatation. We expect that these experiments will contribute to our understanding of Wnt/frizzled signaling in myofibroblast biology and the value of the Wnt/frizzled pathway as a therapeutic target for infarct healing.

We are looking for a candidate with a strong background in life sciences, biochemistry or pharmacy with a clear affinity for pharmacological research. You should be interested in developing novel therapeutic strategies for cardiovascular diseases. We expect from the candidate that he/she either has a permit for animal experiments (“artikel 9 functionaris”) or is willing to obtain this permit. Experience in molecular biological, protein and/or histological techniques would be a benefit.

The terms of employment of Maastricht University are set out in the Collective Labour Agreement of Dutch Universities (CAO). Furthermore, local UM provisions also apply. For more information look at the website http://www.maastrichtuniversity.nl/ , A-Z Terms of Employment.

Temporary employment for 4 years.

Your salary would be € 2.042,-- gross per month in the first year up to € 2.612,-- gross per month in the fourth year according to the PhD-student salary scale.

Each year an evaluation will take place.

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 14,500 students and 3,800 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 Humanities and Sciences, Faculty of Arts and Social Sciences, Faculty of Psychology and Neuroscience.

For additional information, you can contact Dr. Matthijs Blankesteijn, Dept. of Pharmacology, Maastricht University.

e-mail: wm.blankesteijn@maastrichtuniversity.nl

phone: +31 43 3881417