A computer-guided platform for designing sequential cell conversion protocols

• Applicant: Professor Dr. Stefan Stricker
• Subject Area: Bioinformatics and Theoretical Biology ; General Genetics and Functional Genome Biology ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569990124

Neurodegenerative disorders (NDs) represent a heterogeneous group of conditions characterized by the progressive and irreversible loss of functional neurons, with incidence rates steadily increasing worldwide. Emerging strategies in tissue engineering - particularly direct differentiation and cellular reprogramming - have shown promise in addressing these conditions. However, current approaches largely produce neurons with generic, pan-neuronal traits, lacking the subtype-specific features and maturity required for effective functional integration and long-term therapeutic benefit. This limitation likely stems from the constrained number of transcription factors (TFs) deliverable via conventional viral vectors, resulting in reprogrammed neurons with incompletely specified transcriptomic identities. To address this challenge, we propose to develop CIPHER - a computational framework for identifying hierarchical, multi-gene combinations that define specific cell identities and guide high-fidelity, sequential reprogramming protocols. We will apply this framework to three key reprogramming contexts: directed differentiation of mouse globose basal cells, direct conversion of human astrocytes to neurogliaform neurons, and neuronal subtype switching from excitatory to inhibitory fates. Finally, we will employ a novel protein-based CRISPR delivery system (dRNPs) to sequentially activate these gene sets and validate successful, subtype-specific cell fate conversions. Collectively, this integrated approach aims to generate fully specialized, functionally relevant neurons, enhancing the translational potential of cell-based therapies for NDs.

• DFG Programme: Research Grants
• International Connection: Luxembourg
• Partner Organisation: Fonds National de la Recherche
• Cooperation Partner: Professor Antonio del Sol Mesa, Ph.D.