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

在这个翻译项目中，我们遵循临床-实验和基础科学的方法，专注于小纤维病理的诊断和神经病理性疼痛背后的伤害性感受器敏化的病理机制。小口径、稀疏和无髓的A-Delta和C神经纤维是周围神经系统伤害性感受的媒介，其功能和结构可能会受到各种疾病的干扰。由于评估技术的进步，在有或没有神经病理性疼痛的疾病中，关于小神经纤维病理的报告数量正在增加，而潜在的病理生理学仍然不清楚。在我们的项目中，我们专注于小纤维神经病(SFN)，并假设对SFN发病机制的深入分析将使临床和基础科学分层成为可能，这对于理解疾病机制和开发新的诊断和治疗方法至关重要。我们假设皮肤成纤维细胞和角质形成细胞之间的相互作用受损，表皮内伤害性感受器是伤害性感受器敏化的关键，我们的目标是通过一个严格的、多维的项目来验证我们的假设，该项目专门基于患者特定的人类生物材料。在对我们研究队列中的皮肤穿孔活检进行彻底调查的基础上，我们将首先进行详细的组织学分析，采用伤害性感受器可视化的创新方法，然后进行细胞、分子和电生理分析，以确定神经病理性疼痛的目标蛋白。在一种平行的方法中，我们将专注于通过诱导多能干细胞产生的人类来源感觉神经元的互补性研究。我们项目中获得的数据将为未来完全由人类神经支配的三维体外模型铺平道路。在这些完全以患者为基础的系统中获得的知识不仅将加深我们对SFN病理生理学的理解，还将有助于破译皮肤伤害性及其可调性的关键机制。我们的模型将为小纤维病理学领域基于机制的体外研究奠定基础，并将从根本上改善局部止痛化合物的临床前测试。

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.