Translational analysis of the mechanisms underlying small nerve fiber pathology in Fabry disease as a genetically determined model for neuropathic pain

法布里病小神经纤维病理学机制的转化分析作为神经性疼痛的遗传决定模型

• 批准号: 392463150
• 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: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392463150?language=en
• 关键词: Translational; analysis; mechanisms; underlying; small

In this project we will investigate the pathophysiology of neuropathic pain using innovative and directly patient-associated methods. In the peripheral nervous system, nociception is transduced via thinly- and un-myelinated nerve fibers (A-delta and C). Pathophysiological alterations of these nociceptors by acquired or hereditary diseases may lead to neuropathic pain. Neuropathic pain is a cardinal symptom of Fabry disease, a X-chromosomally inherited disorder caused by mutations in the alpha-galactosidase A gene with consecutive lysosomal accumulation of the sphingolipid globotriaosylceramide 3 (Gb3). Based on our previous work we hypothesize that Gb3 interferes with the neuronal ion channel activity and that in parallel peripheral nociceptors are sensitized by inflammatory mediators secreted by surrounding cutaneous cells which together results in the typical neuropathic pain attacks in Fabry disease. We will test this hypothesis in a clinical-experimental approach using fibroblasts and keratinocytes obtained from skin punch biopsies of patients with Fabry disease and healthy controls. For the molecular, histological, and electrophysiological characterization of skin-nerve-neuron interactions we will generate two- and three-dimensional skin models from patient-derived fibroblasts and keratinocytes. These models will then be innervated with neuronal cells obtained from patients` fibroblasts via induced pluripotent stem cells. Data obtained from these completely patient-derived in vitro models will not only fundamentally improve our understanding of neuropathic pain pathophysiology in Fabry disease, but will also allow deciphering basic mechanisms of pain generation in other disorders. Furthermore, these model systems will open entirely novel possibilities for mechanism-based in vitro research including pharmacological testing of locally active potentially neuroprotective and analgesic compounds.

在这个项目中，我们将使用创新的和直接与患者相关的方法来研究神经病理性疼痛的病理生理学。在外周神经系统中，伤害性感觉通过细小的和无髓鞘的神经纤维(A-Delta和C)传递。获得性或遗传性疾病引起的这些伤害性感受器的病理生理改变可能导致神经病理性疼痛。神经病理性疼痛是法布里病的主要症状，法布里病是一种X染色体遗传性疾病，由α-半乳糖苷酶A基因突变和鞘磷脂三糖神经酰胺3(Gb3)溶酶体积累引起。根据我们以前的工作，我们假设Gb3干扰神经元离子通道的活动，同时周围皮肤细胞分泌的炎性介质敏化外周伤害性感受器，共同导致典型的Fabry病的神经病理性疼痛发作。我们将使用从Fabry病患者和健康对照的皮肤穿孔活检中获得的成纤维细胞和角质形成细胞，在临床实验方法中验证这一假设。对于皮肤-神经-神经元相互作用的分子、组织学和电生理特征，我们将从患者来源的成纤维细胞和角质形成细胞产生二维和三维皮肤模型。然后，这些模型将通过诱导多能干细胞从患者的成纤维细胞中获得神经细胞。从这些完全由患者衍生的体外模型中获得的数据不仅将从根本上提高我们对Fabry病的神经病理性疼痛病理生理学的理解，而且还将有助于破译其他疾病中疼痛产生的基本机制。此外，这些模型系统将为基于机制的体外研究开辟全新的可能性，包括局部活性的潜在神经保护和止痛化合物的药理学测试。