PhD candidate 'Maintain Muscle and Brain Dissecting Disrupted Neuromuscular Communication in Myotonic Dystrophy'

• Application Deadline: May 18 2026
• Nijmegen
• On-site

Job Description

Job description

The offered position is a PhD research trajectory within a collaborative project entitled Maintain Muscle and Brain: Dissecting Disrupted Neuromuscular Communication in Myotonic Dystrophy of Radboudumc and Utrecht UMC funded by ZonMw.

Myotonic dystrophy type 1 (DM1) is a chronic multisystem disorder and the most common form of muscular dystrophy in addition to profound involvement of the skeletal muscles there is widespread neurological pathology which includes but is not limited to cognitive deterioration in adults speech disability excessive daytime sleepiness and severe intellectual disability most prominently in the congenital form.

While DM1 is rare it is the most common neuromuscular disorder with a prevalence of 1:2100. The genetic cause of DM1 results from an amplified CTG trinucleotide repeat in the 3 untranslated region of the DMPK gene. It is well accepted that the expanded CTG repeat leads to RNA gain-of-function toxicity by creating long abnormally folded transcripts from the mutant DMPK allele that engage in the formation of abnormal RNA-protein aggregates visible as nuclear foci.

These focal aggregates sequester members of the muscleblind-like family (MBNL1-3) leading to widespread disruptions in RNA metabolism most notably reversion to fetal-like splicing profiles a hallmark of the disease. So far DM1 research has focused mainly on the muscular pathology while current knowledge about molecular and cellular processes that underlie neuromuscular disruptions in DM1 is still in its infancy.

In this project we will investigate the specific pathological consequences at the neuromuscular junction (NMJ). A synergistic and creative new collaboration is established to develop 2D and 3D NMJ models for DM1 consisting of different combinations of patient-induced pluripotent stem cell (hiPSC)-derived neuronal and muscle cells allowing the dissection of pathological processes at the NMJ and their underlying molecular mechanisms. For this we have designed an interdisciplinary research project where fundamental research groups team up in a new collaboration aiming to deliver a multi-faceted view on human DM1 neuro-muscular communication and pathology.

Specific research objectives are:

• Develop a face-valid model for studying the NMJ defects in DM1 by generation of NMJ-on-a-chip and neuromesodermal organoid models.
• Characterize the neurophysiological aberrations induced by DMPK repeat expansions by morphological and molecular characterization of the NMJ and physiological analysis of neuronal and muscle addition this task will include molecular profiling of neuronal and muscular compartments.
• Rescue NMJ disruptions by antisense oligonucleotides enabling reversible correction of this task the PhD candidate will determine the correcting effects of established antisense oligonucleotides and small (candidate) molecules.

Responsibilities include developing and standardizing iPSC-based cell models and analysis of their effect on the neuromuscular junction as well as physiological properties of motoneurons and myofibers.

Other envisaged studies include transcriptomic analyses and investigation of the effect of antisense oligonucleotides and small molecules.

You will develop into an independent scientist and publish scientific publications that together form the PhD thesis. You will present your research at local national and international meetings work collaboratively with other PhD candidates and scientists and engage in research in a stimulating environment including travel to other institutes.

Place of work

The primary working locations are the Departments of Human Genetics (Prof. Dr. H. van Bokhoven) and Medical BioSciences (Dr. D.G. Wansink) at Radboudumc Nijmegen. This project is an intensive collaboration with the Department of Translational Neurosciences UMC Utrecht (Prof. Dr. R.J. Pasterkamp) and part of the research will be conducted there as well.

In the Departments of Genetics and Medical BioSciences you work on research into the mechanisms of hereditary disorders in humans and based on that knowledge the development of new treatments. As leading multidisciplinary departments you conduct high-quality research with impact for patients and their families.