Myotonic dystrophy type 1 (DM1) is the most common inheritable form of muscular dystrophy in adults. Its constellation of symptoms is caused by an expanded (CTG)n repeat in the DMPK gene. There is no cure for DM1 yet, but it is generally accepted that repeat-expanded DMPK RNA is the prime therapeutic target. For the design of effective treatment strategies our understanding of RNA toxicity in DM1 needs refinement. For example, what exactly determines the toxicity of expanded DMPK transcripts? And to which extent must the transcripts of the disease allele be reduced to alleviate symptoms at the cellular level? Hence, we need to identify the contribution of distinct features of expanded DMPK transcripts to RNA toxicity in DM1.

We will apply the CRISPR/Cas9 toolbox to generate muscle cell lines that express expanded DMPK RNAs at different expression levels, with different (CUG)n repeat lengths, and with variable nuclear residence time. We will grow these cells in a biomimetic culture system, approaching the surrounding stimuli of skeletal muscle in patients, to optimize translation of our findings to clinical practice. Cells will be studied under resting, proliferating and differentiating conditions, on different flexible substrates and protein coatings, and under mechanical stimulation to simulate muscle contraction. We thus aim to demonstrate the relevance of separate features of expanded RNA in DM1, which will ultimately help in tailoring drug strategies (e.g., antisense oligonucleotides) to neutralize RNA toxicity.

This project combines complementary expertise from the Myotonic Dystrophy group (Cell Biology) and the Biomaterials group (Dentistry) of the Radboud university medical center.This 4-year-project is funded by the Prinses Beatrix Spierfonds.

• Master's degree (or equivalent) in the field of molecular life sciences and a strong interest in neuromuscular disease and advanced cell (organoid) culture;
• Background in molecular cell biology;
• Experience in molecular and cellular techniques, cell culture and microscopy;
• Motivation, initiative and ambition to publish in high-impact journals;
• Able to work both independently and in multidisciplinary teams at separate locations;
• Excellent communication skills, contributing to a pleasant working atmosphere;
• High level of proficiency in English; basic knowledge of or willingness to learn Dutch.

Expected start date is September-November 2018.

Upon commencement of employment we require a certificate of conduct (Verklaring Omtrent het Gedrag, VOG) and there will be a screening based on the provided CV. Radboud university medical center's HR Department will apply for this certificate on your behalf.

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This research project will be conducted in the Myotonic Dystrophy group of the Department of Cell Biology in collaboration with the Biomaterials group at the Department of Dentistry of the Radboud University Medical Centre, Nijmegen, The Netherlands. The candidate will join the PhD program of the Radboud Institute for Molecular Life Sciences (RIMLS).

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