Awarded a one-year, $100,000 grant from Pachyonychia Congenita Project.
The project aims at improving the understanding of the disease mechanisms involved in painful plantar keratoderma in PC patients. It will compare the expression of genes and proteins involved at a global and cellular level. This study will allow to identify the different cell types and biological pathways responsible for abnormal keratinization and pain. This work has the potential to uncover new therapeutic targets and will guide repurposing of existing drugs for PC patients.
Project Title: Integrative mRNA sequencing, proteomics and phosphoproteomics in pachyonychia congenita
Principal Investigator (PI) Name: Alain Hovnanian, MD, PhD
PI Affiliations: Inserm UMR1163
PC is a rare genodermatosis characterized by very painful palmoplantar keratoderma, oral leukokeratosis, nail dystrophy and cysts. It is caused by dominant mutations in keratin genes KRT6A, KRT6B, KRT6C, KRT16, and KRT17. The understanding of PC pathophysiology is incomplete despite recent progress. There is no cure for PC and current treatment options are limited. This project aims at better understanding the pathophysiology of pachyonychia congenita (PC) by combing mRNA sequencing, proteomic and phosphoproteomic studies in PC-affected and unaffected skin to
guide new therapeutic repositioning strategies. The hypothesis to be tested is that Epidermal Growth Factor Receptor (EGFR) activation plays a major but not exclusive role in PC pathogenesis and that the identification of additional pathways and/or mechanisms of activation of the EGFR pathway and its consequences may identify new therapeutic targets. We have already collected skin biopsies from lesional (plantar calluses) and non lesional skin (healthy sole) from 3 PC patients to perform a preliminary study aiming at optimizing bulk and single-cell mRNA sequencing (scRNAseq), as well as proteomic and phosphoproteomic analyses. These patients have mutations in KRT6A and KRT16 genes. In the first part of the project we will optimize bulk mRNA sequencing, single-cell RNA sequencing, proteomic and phosphoproteomic techniques from existing frozen OCT-embedded lesional and non-lesional skin biopsies. The information generated in the pilot study will be used to minimize the number and size of skin biopsies to achieve mRNA sequencing, proteomic and phosphoproteomic studies in 7 to 10 PC patients. This study should allow to identify the different cell types and biological pathways involved in PC pathophysiology at the transcriptomic and proteomic levels. Phosphoproteomics will help deciphering active pathways including the EGFR pathway. This multimodal and integrative profiling of PC lesional skin has the potential to uncover new therapeutic targets and will guide therapeutic repurposing.