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，专注于小纤维病理学的诊断和伤害感受器敏化神经性疼痛的病理机制。小口径、薄且无髓鞘的A-δ和C神经纤维是周围神经系统中的伤害感受介质，其中它们的功能和结构可被各种疾病干扰。鉴于评估技术的进步，在伴有和不伴有神经性疼痛的疾病中，关于小神经纤维病理学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病理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与表皮内伤害感受器之间的串扰受损是伤害感受器致敏的关键，目的是用一个严格的、多维的项目来测试我们的假设，该项目完全基于患者特异性的人类生物材料。基于对我们研究队列的皮肤穿刺活检的彻底调查，我们将首先采用创新的伤害感受器可视化方法进行详细的组织学分析，然后进行细胞，分子和电生理分析，以确定神经性疼痛的靶蛋白。在一个平行的方法，我们将专注于通过诱导多能干细胞产生的人源性感觉神经元的补充调查。本研究所获得的数据将为未来的全人神经支配的三维体外模型铺平道路。在这些完全基于患者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，而且还将允许破译皮肤伤害感受及其可修改性的关键机制。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镇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.