MSCA-DN PhD position in Molecular Pharmacology (Amsterdam, NL)

POLARIS is a European Marie Skłodowska-Curie Doctoral Network focused on accelerating therapy development for leukodystrophies: rare genetic disorders affecting the brain's white matter. The network aims to strengthen the full translational pathway, from understanding disease mechanisms and developing disease models to preclinical therapy testing, clinical readiness and patient-informed treatment priorities.

To achieve this, POLARIS brings together expertise in leukodystrophy biology, advanced disease models, therapeutic innovation, biomarker development, clinical translation, patient engagement, and ethical, regulatory and health-economic aspects of therapy development. The network will train a cohort of doctoral candidates in an international and interdisciplinary environment, combining academic research, industry-based preclinical development, secondments, network-wide training and transferable-skills development.

PhD project
The project is based within the Medicinal Chemistry research group at Vrije Universiteit Amsterdam. You will investigate the molecular pharmacology of an orphan G protein-coupled receptor (GPCR) as a potential drug target for megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare genetic brain disease that affects mechanisms regulating brain volume.

MLC currently has no available drug treatment. The orphan GPCR was recently identified as a potential drug target in a subgroup of people with MLC by researchers in Pediatric Neurology at Amsterdam UMC. GPCRs are cell-surface proteins that respond to external stimuli and are widely investigated as drug targets.

The aim of the project is to understand how the orphan receptor is activated and signals, develop high-throughput screening assays and identify drug-like modulators. You will use FDA-approved drug library repurposing and fragment-based drug discovery (FBDD) to search for potential modulators.

As part of the POLARIS doctoral network, you will develop a functional GPCR assay pipeline to support the identification of modulators and understand their mode of action. Promising pharmacological modulators can ultimately be tested in cellular and in vivo models of disease.

Planned secondments will provide hands-on experience in in vitro assay validation and in vivo characterisation of lead molecules.

You will use molecular receptor pharmacology techniques to investigate the orphan GPCR and its potential as a therapeutic target. Your work will include:

• Developing cell-based bioluminescent and fluorescent biosensor assays to detect GPCR signalling events in different cellular models.
• Investigating receptor activation and signalling mechanisms.
• Developing and applying high-throughput screening assays to identify potential drug-like modulators.
• Using FDA-approved drug library repurposing and fragment-based drug discovery to identify and characterise promising compounds.
• Contributing to the development of a functional GPCR assay pipeline and the evaluation of lead molecules in collaboration with POLARIS partners.