Promovendus bij de Faculteit Health, Medicine and Life Sciences, School CAPHRI, Vakgroep Gezondheidsbevordering
Ongeveer 6 uur geleden - Universiteit Maastricht - Maastricht
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.
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:
Scale 10A: max. € 40814 gross income per year at full employment (incl. vacation bonus and end of year payments)
The second job interview will conduct a writing assessment and presentation.
All additional information about the vacancy can be obtained from Dr. Ellen van den Bogaard and Dr. Patrick Zeeuwen, principal investigators at the Department of Dermatology. Use the Apply button to submit your application.
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.
Read more about the Radboudumc employment conditions.
We request applicants to send a letter of intent outlining special interest in the position, overall related qualifications, experience and career goals, a curriculum vitae and names and addresses of professional references.
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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:
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.