Project 2: Influence of Scratching on Skin Profiles in Chronic Pruritus Patients
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Chronic pruritus (CP) is a highly prevalent symptom of many different diseases and its underlying pathobiological mechanisms remain unclear. CP is characterized by a high burden of suffering for patients globally, including a high negative impact on their quality of life. Still, effective therapy modalities are missing due to the fact that little is known about the pathways which underlie CP. This holds especially true for the mechanisms that are involved in the different entities (such as inflammatory, neuropathic and systemic types of CP) and for the mechanisms that promote chronicity of pruritus in general. One factor, which has been neglected in research until now, is the impact of scratching on the course of pruritus and on the peripheral neuronal sensitization.
Scratching is a hallmark of acute and chronic pruritus and frequently leads to visible damage and alterations of the skin. The influence of scratching on the cellular and molecular mechanisms of itch in humans has, until now, never been systematically investigated. This is the major aim of this patient-oriented project. We aim to identify cutaneous neuro-anatomic changes and specific neuronal and non-neuronal pruritic markers in respect to chronic scratching. To this purpose, we will recruit patients with different types of chronic pruritus, such as pruritus due to an inflammatory dermatosis (atopic dermatitis), neuropathic pruritus (brachioradial pruritus, notalgia paresthetica) and systemic pruritus (uremic pruritus). 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, expression of pruritogenic markers (e.g. gastrin releasing peptide, TRP channels) and the cutaneous gene expression profiles by means of mRNA sequencing.
To obtain a functional correlate in the scratched and unscratched skin, focal electrical stimulation will be performed for selective nociceptor stimulation. In project #6, using the same patients and controls, cowhage stimulation and quantitative sensory testing will be performed on the same skin areas (chronically scratched; unscratched; normal skin) allowing a comprehensive functional characterization of pruriceptors and nociceptors. Upon a subsequent in vivo (biopsies of a longitudinal study of project #1) and in vitro (stimulation with pruritogenic and/or neurogenic factors in a co-culture model of keratinocytes and neurites) approach, relevant factors which have been determined by the previous experiments will be analyzed.
Finally, 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.
Scratching is a hallmark of acute and chronic pruritus and frequently leads to visible damage and alterations of the skin. The influence of scratching on the cellular and molecular mechanisms of itch in humans has, until now, never been systematically investigated. This is the major aim of this patient-oriented project. We aim to identify cutaneous neuro-anatomic changes and specific neuronal and non-neuronal pruritic markers in respect to chronic scratching. To this purpose, we will recruit patients with different types of chronic pruritus, such as pruritus due to an inflammatory dermatosis (atopic dermatitis), neuropathic pruritus (brachioradial pruritus, notalgia paresthetica) and systemic pruritus (uremic pruritus). 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, expression of pruritogenic markers (e.g. gastrin releasing peptide, TRP channels) and the cutaneous gene expression profiles by means of mRNA sequencing.
To obtain a functional correlate in the scratched and unscratched skin, focal electrical stimulation will be performed for selective nociceptor stimulation. In project #6, using the same patients and controls, cowhage stimulation and quantitative sensory testing will be performed on the same skin areas (chronically scratched; unscratched; normal skin) allowing a comprehensive functional characterization of pruriceptors and nociceptors. Upon a subsequent in vivo (biopsies of a longitudinal study of project #1) and in vitro (stimulation with pruritogenic and/or neurogenic factors in a co-culture model of keratinocytes and neurites) approach, relevant factors which have been determined by the previous experiments will be analyzed.
Finally, 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.
Related Publications:
- Huck V, Gorzelanny C, Thomas K, Getova V, Niemeyer V, Zens K, Unnerstall TR, Fegera JS, Fallah MA, Metze D, Ständer S, Luger TA, Koenig K, Mess C, Schneider SW. From morphology to biochemical state – intravital multiphoton fluorescence lifetime imaging of inflamed human skin. Sci Rep. 2016; 6:22789 [IF 4.259]
- Iking A, Grundmann S, Chatzigeorgakidis E, Phan NQ, Klein D, Ständer S. Prurigo nodularis as a symptom of atopic and non-atopic diseases: etiological survey in a consecutive cohort of 108 patients. J Eur Acad Dermatol 2013;27: 550-7 [IF 3.528]
- Haas S, Capellino S, Phan NQ, Böhm M, Luger T Straub RH, Ständer S. Low density of sympathetic nerve fibers relative to substance P-positive nerve fibers in lesional skin of chronic pruritus and prurigo nodularis. J Dermatol Sci 2010; 58:193-197 [IF 3.733]
- Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the neurokinin receptor 1 with aprepitant: A novel antipruritic strategy. PLoS One 2010; 5: e10968. [IF 2.806]
- Schuhknecht B, Marziniak M, Wissel A, Phan NQ, Pappai D, Dangelmaier J, Metze D, Ständer S. Reduced intraepidermal nerve fiber density in lesional and non-lesional prurigo nodularis skin as po-tential sign of subclinical cutaneous neuropathy. Br J Dermatol 2011; 165:85-91 [IF 4.706]
- Marziniak M, Phan NQ, Raap U, Siepmann D, Schürmeyer-Horst F, Pogatzki-Zahn E, Niederstadt T, Ständer S. Brachioradial pruritus as a result of cervical spine pathology: results of a magnetic resonance tomography study. J Am Acad Dermatol 2011; 65: 756-62 [IF 7.002]
- Huesmann T, Cunha PR, Osada N, Huesmann M, Zanelato TP, Phan NQ, Abreu Gontijo GM, Marziniak M, Ständer S. Notalgia paresthetica: a descriptive two-cohort study of 65 patients from Brazil and Germany. Acta Derm Venereol 2012; 92: 535-540 [IF 3.653]
- Ständer S, Schmelz M, Metze D, Luger T, Rukwied R. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci. 2005; 38: 177-88. [IF 3.733]
- Bobko S, Zeidler C, Osada N, Riepe C, Pfleiderer B, Pogatzki-Zahn E, Lvov A, Ständer S. Intraepidermal Nerve Fibre Density is Decreased in Lesional and Inter-lesional Prurigo Nodularis and Reconstitutes on Healing of Lesions. Acta Derm Venereol. 2016; 96: 404-406. [IF 3.653]
- Agelopoulos K, Richter GH, Schmidt E, Dirksen U, von Heyking K, Moser B, Klein HU, Kontny U, Dugas M, Poos K, Korsching E, Buch T, Weckesser M, Schulze I, Besoke R, Witten A, Stoll M, Köhler G, Hartmann W, Wardelmann E, Rossig C, Baumhoer D, Jürgens H, Burdach S, Berdel WE, Müller-Tidow C. Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma. Clin Cancer Res. 2015;21(21):4935-46 [IF 9.619]