Awarded a one-year, $100,000 grant from Pachyonychia Congenita Project.
Of all of the features of Pachyonychia Congenita, pain in the hands and feet arguably has the most negative impact on quality of life, and is frustratingly difficult to treat. We propose to use genetically engineered mice that mimic PC or similar hereditary skin disorders to pinpoint the molecules that drive the exaggerated pain sensation. Armed with this information, the field will be able to identify new strategies to block those molecules and diminish pain in individuals with PC and possibly other related painful skin conditions.
Project Title: Identifying Molecular Drivers of Pain in Hereditary Palmoplantar Keratodermas
Principal Investigator (PI) Name: Michael J. Caterina, MD, PhD
PI Affiliations: Dept Neurosurgery, Johns Hopkins University School of Medicine
Abstract
Pain is the most life-impacting feature of Pachyonychia Congenita and some other hereditary palmoplantar keratodermas. Unfortunately, pain in individuals with PC is often refractory to treatment. A better understanding of specific mechanisms driving pain in PC and other hereditary PPKs might inform rational strategies to diminish such pain. We have found that several mouse models of hereditary PPKs exhibit a spectrum of pain phenotypes. SLURP1 and SLURP2 knockout mice, which model Mal de meleda and Krt16 knockout mice, which model PC, both show enhanced spontaneous and evoked pain behaviors. Conversely, Krt9 knockout mice, which model Epidermolytic PPK, do not. Using transcriptomic analysis, we identified a subset of genes that are dysregulated in the sensory neurons of both SLURP knockout and Krt16 knockout mice, but not in Krt9 knockouts, suggesting that there is a specific transcriptomic pattern associated with pain in these mouse strains. Here, we propose to define this pattern more comprehensively, taking into account the pronounced heterogeneity of sensory neurons, by performing single-cell RNAseq. This method will allow us to define with great precision which genes are differentially expressed in painful vs. nonpainful PPK models and which of these changes occur in sensory neuron subtypes relevant to pain. We will validate the most promising of these changes using orthogonal methods. Our study will provide an unprecedented view of how PPK alters gene expression in pain-regulating neurons innervating the skin and how this differs in painful and nonpainful PPK, and help identify specific molecules as candidate targets for alleviation of pain in PC and other PPKs.
