PhD position in EU Doctoral Network "PANDORA". Discovering pathomechanisms and novel drug optimisation for AMD (DC10)

About this position

Phenotypic drug discovery in age-related macular degeneration (AMD)

The PhD position is part of the MSCA Doctoral Network PANDORA , focused on discovering Pathomechanisms and Novel Drug Optimization for AMD (Age-Related Macular Degeneration).

Oxidative stress is a major contributor to retinal pigment epithelium (RPE) dysfunction in age-related macular degeneration (AMD) and may interact with genetic risk associated with dysregulation of the complement system, including the CFH Y402H risk variant. The PhD student will develop disease-relevant cellular models and phenotypic drug-screening approaches to identify and characterize compounds capable of protecting RPE cells from oxidative stress and complement-associated damage.

A central component of the project will be the culture and differentiation of human induced pluripotent stem cells (iPSCs) into retinal pigment epithelial (iPSC-RPE) cells , followed by morphological, molecular and functional characterization of the resulting RPE models. These models will be used to investigate oxidative stress-associated phenotypes and to validate compounds identified through screening.

The PhD student will establish high-throughput screening assays using oxidative stress-induced cellular models and screen a library of antioxidant and redox-modulating compounds , including a selected subset of microbial natural products from the MEDINA collection. Active compounds will be confirmed through concentration-response studies and subsequently evaluated in disease-relevant iPSC-RPE models.

The compounds identified as protective against oxidative stress will undergo detailed validation and phenotypic characterization to investigate their protective activity and mechanisms of action.

The project will make extensive use of High-Content Imaging and Cell Painting to generate multiparametric morphological profiles reflecting cellular responses to oxidative stress and compound-mediated phenotypic rescue. The doctoral candidate will perform quantitative analysis of high-dimensional imaging datasets using computational and bioinformatic approaches, including image-derived feature processing, dimensionality reduction and phenotypic clustering. These analyses will contribute to identifying compound-specific phenotypic signatures and investigating mechanisms of action.

The most promising compounds will subsequently be evaluated in advanced genetic models of complement-mediated AMD developed within the PANDORA network.

The doctoral candidate will utilize cutting-edge techniques:

• Human iPSC culture and differentiation into RPE
• Characterization of iPSC-derived RPE using molecular, morphological and functional assays
• Mammalian cell culture and oxidative stress models
• High-throughput compound screening and dose-response studies
• High-Content Imaging and Cell Painting
• Automated image analysis and multiparametric phenotypic profiling
• Bioinformatic and statistical analysis of high-dimensional imaging datasets
• Molecular and biochemical assays to characterize oxidative stress, mitochondrial function and cellular damage
• Bioactivity characterization and mechanism-of-action studies

The position will provide state-of-the-art training at the interface of stem cell biology, retinal disease modelling, phenotypic drug discovery, high-content imaging and computational biology , within the highly interdisciplinary and international environment of the PANDORA Doctoral Network.

Open Access research publications related to this position:

https://pubmed.ncbi.nlm.nih.gov/40384930/

https://pubmed.ncbi.nlm.nih.gov/39981241/

https://pubmed.ncbi.nlm.nih.gov/34155630/

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=7511696