Targeting CDK4/6 for the treatment of skin diseases (B09)

• Subject Area: Immunology ; Dermatology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246807620

In the previous funding period, we have identified keratinocyte-derived IκBζ, a transcriptional cofactor of NF-κB, as a central driver of psoriasis, which is regulated by the cyclin-dependent kinases CDK4 and CDK6. Consequently, topical application of a CDK4/6 inhibitor suppresses IκBζ expression in the skin thereby resolving experimentally induced psoriasis. The planned project aims at the development of CDK4/6 inhibitors with optimized properties for topical application (Aim 1). Optimized compounds will be formulated as an ointment, which will be subsequently tested in vitro and in vivo to investigate its effects on psoriasis, skin homeostasis, and S. aureus skin infections (Aim 2). Since the function of these two CDKs in skin immunity has not been investigated yet, we will generate tissue-specific CDK4- and CDK6-deficient mice, and investigate the impact of CDK4/6 deficiency in single skin cell types at steady state but also during psoriasis-like skin inflammation (Aim 3). In the end, our project will deliver an optimized CDK4/6 inhibitor for topical treatment of skin diseases, such as psoriasis, but also reveal new insights into the role of CDK4/6 in skin immunity.

• DFG Programme: CRC/Transregios
• Subproject of: TRR 156: The skin as sensor and effector orchestrating local and systemic immunity
• Applicant Institution: Ruprecht-Karls-Universität Heidelberg
• Project Heads: Professor Dr. Matthias Gehringer, since 7/2023; Professor Dr. Stephan Hailfinger, until 6/2023; Dr. Daniela Kramer