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

角质形成细胞和成纤维细胞对表皮内神经纤维的生长调节和轴突敏化作用的研究

• 批准号: 280178488
• 负责人: Professorin Dr. Nurcan Üçeyler
• 金额: --
• 依托单位: Neurologische Klinik und Poliklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280178488?language=en
• 关键词: Investigation; growth; modulating; axon; sensitizing

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.

小纤维神经病（Small fiber neuropathies，SFN）是感觉神经病的一个亚类，以小口径A-δ和C-神经纤维的功能损害为特征，伴有脚趾和足部的局部烧灼痛。典型的组织学表现是表皮内神经纤维（IENF）减少或完全丧失。据推测，角质形成细胞和成纤维细胞在SFN局灶性神经病理性疼痛的诱导和维持中起着积极的作用。目前尚不清楚为什么IENF退化，伤害感受器的减少和丢失如何导致疼痛增加，以及为什么IENF密度与疼痛程度无关。该项目中遵循的假设是角质形成细胞和成纤维细胞通过分泌轴突导向蛋白如netrin来调节轴突生长，并且这些皮肤netrin诱导角质形成细胞和成纤维细胞产生痛觉促炎细胞因子。然后这些细胞因子可以激活剩余的IENF并诱导疼痛。该假设将通过临床和实验方法进行测试，使用从SFN患者与健康对照相比的皮肤穿刺活检获得的角质形成细胞和成纤维细胞培养物。角质形成细胞和成纤维细胞与神经炎的相互作用将在寡隔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，并为新的治疗策略提供潜在的目标。