This project focuses on the role of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, in maintaining and restoration epithelial integrity of the skin. Activation of AHR signaling can be considered as a ‘key-lock’ principle: structurally diverse ligands (keys) can activate the AHR (lock) resulting in various downstream signaling pathways. In the past, the AHR was considered to mediate the metabolism of xenobiotics and was predominantly associated with toxicity. The discovery of endogenous AHR ligands revealed a physiological role of the AHR in cell behavior and development and sparked a renewed strong interest in this receptor. Nowadays, the AHR is considered a therapeutic target in many research fields, and clinical trials with AHR ligands for inflammatory diseases are ongoing.
 
Our group identified a key role for the AHR in regulating epidermal differentiation and proliferation. We found AHR activation to be indispensable for the therapeutic effect of coal tar, one of the oldest dermatological therapies for inflammatory skin diseases (e.g. eczema and psoriasis). The identification of the AHR-dependent therapeutic effects of coal tar led us to study the therapeutic activity of novel AHR ligands and to investigate the downstream effects of AHR signaling in keratinocytes (epidermal skin cells) using genome wide chromatin-immunoprecipitation followed by sequencing (ChIP-seq) and RNA sequencing (RNA-seq).

We identified several structurally diverse AHR ligands to have therapeutic effects in in vitro skin models for eczema. Importantly, these ligands did not show signs of cell toxicity or genotoxicity. By cluster and Gene Ontology analysis of the ChIP-seq and RNA-seq data we found the AHR to interact with other important transcription factors and signaling pathways to regulate the expression of genes involved in the cell cycle, keratinocyte differentiation and host defense responses.

The aim of this multifaceted research project is to unravel the signaling molecules and pathways upon AHR activation in keratinocytes, based on the aforementioned genome-wide data analysis. Functional analysis of the mechanisms involved in the keratinocyte response to AHR ligands will lead to the identification of novel AHR target genes and proteins involved in the AHR-mediated effects on epithelial integrity.  We anticipate that these studies will lead to new therapeutic targets for inflammatory skin diseases and these will be further investigated and validated in this project using advanced in vitro and in vivo models for eczema and psoriasis. Pre-clinical studies with the novel AHR ligands should generate sufficient data for first-in-man clinical studies and pilot studies in patients. This four-year project should culminate in a PhD thesis.

Tasks and responsibilities
The PhD candidate:

• Contributes to the development of new knowledge within the context of the department’s research program;
• Designs and performs scientific research;
• Writes scientific publications and presents findings at scientific meetings;
• Works in a team with clinical and non-clinical PhD candidates and scientists;
• Discusses, plans and performs research in a stimulating environment.

Profile

• Master’s degree in preferably Molecular life sciences or equivalent;
• Experience in cell culture;
• Experience in molecular biology, affinity with bioinformatics;
• Art. 9 degree in animal studies is a prerequisite;
• Enthusiasm and ambition to succeed in academic research and motivated to work a few months abroad (USA) during the project;
• Highly motivated to work in an interdisciplinary environment and to work with other researchers outside the department;
• Well-developed social skills directed to work in a team, excellent interpersonal and communicative skills;
• You recognise yourself in the Radboud way of working.

Fixed-term contract: 4 years.

Scale 10A: max. € 40814 gross income per year at full employment (incl. vacation bonus and end of year payments)

Radboudumc (university medical center)

Radboudumc strives to be a leading developer of sustainable, innovative and affordable healthcare to improve the health and wellbeing of people and society in the Netherlands and beyond. This is the core of our mission: To have a significant impact on healthcare. To get a better picture of what this entails, check out our strategy film.

Our key strength is medical life-sciences and clinical practice, with an impressive infrastructure comprising state-of-the-art technology platforms and (translational) research facilities. The Radboudumc is therefore uniquely positioned in the emerging Euregio and Dutch healthcare infrastructure to play a leading role in the new healthcare paradigm of prediction, prevention and personalised medicine.

The Radboudumc focuses on scientific health challenges of today, with an eye on emerging diseases of the future.

Read more about what it means to work at Radboudumc and how you can do your part.

https://www.radboudumc.nl/EN/Pages/default.aspx

The research project will be conducted at the Experimental Dermatology Laboratory, Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands. We focus on the interplay of the skin with the environment in relation to the pathophysiology of highly prevalent inflammatory skin diseases such as psoriasis and eczema.

Our research program has a strong translational character and  includes the following research lines of mainly hypothesis-driven research:

1. Development of state-of-the-art 3D skin models by tissue engineering of human skin in combination with patient-derived cells or keratinocyte cell lines modified by CRISPR-Cas9 technology
2. Functional analysis of genetic risk factors for inflammatory skin diseases
3. Gene-host-microbe interactions in skin health and disease
4. Identification and implementation of novel therapeutic targets or compounds for inflammatory skin diseases

Our research is embedded in the Radboud Institute for Molecular Life Sciences (RIMLS). The studies indicated in this vacancy will be performed in close collaboration with other research groups within the RIMLS and with the Perdew laboratory at the Pennsylvania State University (USA). We provide a stimulating work environment within a group of enthusiastic non-clinical and clinical researchers with a strong national and international research network and track record.