Translational and multidimensional analysis of the mechanisms underlying nociceptor sensitization in small fiber pathology

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In this translational project, we follow a clinical-experimental and basic science approach focusing on the diagnosis of small fiber pathology and the pathomechanism of nociceptor sensitization underlying neuropathic pain. The small caliber, thinly- and unmyelinated A-delta and C nerve fibers are mediators of nociception in the peripheral nervous system where their function and structure can be disturbed by diverse diseases. Given the advances in assessment techniques, the number of reports on small nerve fiber pathology are increasing in disorders with and without neuropathic pain, while the underlying pathophysiology remains obscure. In our project, we concentrate on small fiber neuropathy (SFN) and hypothesize that in depth analysis of SFN pathomechanisms will enable clinical and basic science stratification which is crucial for understanding disease mechanisms and the development of novel diagnostic and therapeutic approaches. We assume impaired cross-talk between skin fibroblasts and keratinocytes with intraepidermal nociceptors key for nociceptor sensitization, and aim at testing our hypothesis with a demanding, multidimensional project exclusively based on patient-specific, human biomaterial. Grounded on the thorough investigation of skin punch biopsies from our study cohort, we will first undertake detailed histological analysis with innovative approaches for nociceptor visualization, which will then be followed by cellular, molecular, and electrophysiological analysis to identify target proteins for neuropathic pain. In a parallel approach, we will focus on the complementary investigation of human-derived sensory neurons generated via induced pluripotent stem cells. Data obtained in our project will pave the way for future fully human innervated three-dimensional in vitro models. The knowledge gained in these entirely patient-based systems will not only deepen our understanding of SFN pathophysiology, but will also allow deciphering key mechanisms of cutaneous nociception and its modifiability. Our models will lay the ground for mechanism-based in vitro research in the field of small fiber pathology, and will fundamentally improve pre-clinical testing of topical analgesic compounds.