Investigation of the growth-modulating and axon-sensitizing effect of keratinocytes and fibroblasts on intraepidermal nerve fibers

小纤维神经病变（SFN）是感觉神经病变的一个亚群，其特征是小径a - δ和c神经纤维的功能损害，并伴有脚趾和足部局部灼痛。典型的组织学表现是表皮内神经纤维（IENF）减少或完全丧失。假设角化细胞和成纤维细胞在SFN局灶性神经性疼痛的诱导和维持中起积极作用。目前尚不清楚IENF退化的原因，伤害感受器的减少和丧失如何导致疼痛增加，以及为什么IENF密度与疼痛程度无关。本项目的假设是，角化细胞和成纤维细胞通过分泌轴突引导蛋白如网状蛋白来调节轴突生长，这些皮肤网状蛋白诱导角化细胞和成纤维细胞产生促炎性细胞因子。这些细胞因子可能会激活剩余的IENF并引起疼痛。这一假设将通过临床和实验方法进行验证，将SFN患者皮肤穿刺活检获得的角质细胞和成纤维细胞培养物与健康对照进行比较。角化细胞和成纤维细胞与神经炎的相互作用将在寡隔间共培养系统中进行分析。这些发现将提高对疼痛病理生理学的理解，并将为新的治疗策略提供潜在的目标。

Small fiber neuropathies (SFN) are a subgroup of sensory neuropathies, which is characterized by functional impairment of small caliber A-delta and C-nerve fibers with localized burning pain at toes and feet. The typical histological finding is a reduction or a complete loss of the intraepidermal nerve fibers (IENF). It is assumed that keratinocytes and fibroblasts play an active role in the induction and maintenance of focal neuropathic pain in SFN. It is unclear why IENF degenerate, how reduction and loss of nociceptors leads to increased pain, and why IENF density does not correlate with the extent of pain. The hypothesis followed in this project is that keratinocytes and fibroblasts modulate axonal growth by the secretion of axon guidance proteins like netrins and that these cutaneous netrins induce the production of algesic pro-inflammatory cytokines by kerationocytes and fibroblasts. These cytokines may then activate the remaining IENF and induce pain. This hypothesis will be tested with a clinical and experimental approach using keratinocyte and fibroblast cultures obtained from skin punch biopsies of patients with SFN compared to healthy controls. The interaction of keratinocytes and fibroblasts with neuritis will be analyzed in oligo-compartimented co-culture systems. The findings will improve the understanding of pain pathophysiology and will provide potential targets for new therapy strategies.