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Influence of scratching on skin profiles

Influence of scratching on skin profiles in chronic pruritus patients

Konstantin Agelopoulos, Sonja Ständer

Chronic pruritus (CP) is a highly prevalent symptom of different diseases and constitutes a high burden of suffering for patients. Still, little is known about the underlying pathways. This holds especially true for the mechanisms involved in scratching. Scratching reliefs pruritus but, in CP, it can result in damage of the skin integrity, anatomy and function. The influence of scratching on the cutaneous cellular and molecular mechanisms and chronicity of pruritus has, until now, never been systematically investigated. In this project, we aim to analyze the epidermal neuroanatomical alterations, and neuronal and non-neuronal pruritic markers that are induced by scratching. We will further investigate the effect of chronic mechanical stress (as equivalent for scratching) on gene expression regarding factors contributing to nerve fiber alterations and metabolism of keratinocytes and we will define the role of long-term modifying factors of gene expression in maintaining chronicity of pruritus.

We will recruit patients with chronic nodular prurigo (CNPG, syn: prurigo nodularis; as a model for severe scratch-related skin lesions), atopic dermatitis (AD; in order to connect to data obtained in the first funding period) and corresponding healthy volunteers (in total 180 participants). Using skin biopsies of (a) pruritic, chronically scratched, (b) pruritic, unscratched and (c) not-pruritic, normal skin, we will morphologically characterize the neuroanatomy of the cutaneous nerve fibers and expression of pruritogenic markers. We will isolate keratinocytes to analyze in vitro the effect of chronic mechanical stress on gene expression. This will be done by means of mRNA sequencing with focus on neuroplasticity- related genes. Comparison of the different areas will enable us to identify a priming effect of pruritus and chronic scratching on these cells. Co-culture of neuronal cells and the keratinocytes will be used for functional validation of candidate genes defined within the first funding period. We will use spiking or depletion in media (secreted proteins) or modulation of gene expression. To obtain a functional correlate in the scratched and unscratched skin, focal electrical stimulation will be performed for selective nociceptor stimulation. Finally, DNA methylation signatures will be defined for the different CP entities as well as for chronic scratching. Analyzing same biopsies will allow to define impact of DNA methylation on gene expression profiles and by this on maintaining chronicity.

In sum, we aim to identify the causal relationships between the scratching-related factors and morphological changes, clinical pruritus characteristics obtained via questionnaires and functional parameters. The findings will have an important translational impact by defining molecular factors which are related to chronic scratching and which open novel therapeutically strategies.