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FOR 2690:  Translational Pruritus Research

Subject Area Medicine
Term since 2018
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 350193106
 
Treatment of chronic pruritus is an unmet clinical need in patients with dermatological diseases, neuropathy, cholestasis and renal failure. It severely reduces quality of life and is difficult to treat. New major discoveries have identified functional markers for primary pruriceptive afferent neurons (Mrgpr family), peripheral mediators linked to the itch sensation (IL-31, LPA, TSLP) and central transmitters specific for itch processing (BNP, GRP). However, there is also clinical evidence for targets common for nociceptors and pruriceptors (NK1, NaV1.7). Upon translation of this new experimental knowledge from rodents to patients we are facing three major challenges: a) Which of the markers and mediators found in rodents are crucially involved in itch processing in chronic itch patients? b) Itch can be elicited by activation of pruriceptors (“labeled line”), but also nociceptors can generate itch (“pattern theory”); therefore human studies are required to answer the question whether therapeutic targets in humans should be investigated primarily in nociceptors or in specific pruriceptors c) Patients report combined itch and pain sensations both in neuropathic and inflammatory itch conditions, but currently there is no consensus on diagnostic approaches and treatment between the involved disciplines. Therefore, a common concept is required that allows either a clear separation of the entities or alternatively comprehensively describes their overlap.New national and international networks on itch research were established to combine efforts of clinicians and basic researchers bridging various disciplines. For our projects, we took advantage of these multidisciplinary approaches and our long-standing research collaborations to select domestic experts in dermatology, neurology, anesthesiology, gastroenterology, immunology, radiology, and neurophysiology required to approach the complex challenges. Our projects cover three key perspectives on clinical itch: signaling of pruritus (including mediator release from non-neuronal cells and activation of primary afferents), neuronal heterogeneity (differentiating pruriceptors and nociceptors) and neuropathic changes leading to chronic itch and pain. Based on clinical relevance and existing knowledge on pathophysiology, we will focus on major clinical itch conditions: inflammatory (atopic eczema), neuropathic (brachioradial pruritus, notalgia paresthetica) and non-inflammatory (cholestatic pruritus) chronic pruritus. According to the clinical clinical problem, we chose a patient-centered approach in which translational electrophysiological studies provide nociceptor class specific stimulation protocols for the clinical projects.Ultimately, by unifying the currently separated clinical approach between chronic itch (dermatology) and chronic pain (neurology, anesthesiology) we expect to identify common mechanisms of neuronal sensitization that open up new treatment options.
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